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REVIEW OF THE STRUCTURAL REQUIREMENTS FOR SYMPATHOMIMETIC DRUG ACTION A. M. Lands Pharmacology Section of the Sterling-Winthrop Research Institute Rensselaer, New York
74 A review of sympathomimetic amines, summarizing briefly a half-century of investigation, is appropriate at this time inasmuch as research in this field may be considered to have begun with the present century. Epinephrine ('Suprarenin1, adrenalin) was isolated from the adrenal gland by Abel and Crawford1, Aldrich5 and Takamine10^ in the years 1899 - 1902. Chemical constitution was soon determined and synthesis followed in 1905Z7,89 Resolution of the racemic salt into its optical isomers was first described by Flacher32 in 1908. This early research has been reviewed in some detail by TrendelenburglO7 amj by Hartung. 4* The investigations of Barger and Dale'*, published in 1909-10, extended greatly the field of investigation and emphasized the possibility of obtaining important new sympathomimetic drugs through synthesis. The intervening years have witnessed the appearance of a legion of synthetic compounds which influence activity of organs innervated by the sympathetic nervous system. In this communication, more than two hundred sympathomimetic amines have been reviewed and the significant pharmacologic "screening" data are listed in tables. Although the experimental results obtained by different investigators are often at variance, probably due to dissimilar test procedures and different criteria of effectiveness, the tabulated data will give a general indication of the relative potencies and toxicities. The text tables have been designed to emphasize the importance of variations in chemical structure on sympathomimetic action. Effects on blood pressure and toxicity have been most extensively investigated and will be considered first in this communication. The Effnt of Structural Modification of Sympathomimetic Amines on Vasopressor Action and Toxicity Barger and Dale'* established the importance of the basic group, p-phenylethylamine, for vasopressor action. The close analogs, a-phenylethylamine (No. 2), p-phenylisopropylamine (No 5) and v-phenylpropylamine (No. 4) have been reported by most investigators to be distinctly less potent (Table I). Benzylamine (No. 1) and a-phenylpropylamine (No. 7) are like- wise very weak vasopressor agents. Methyl substitution at the alpha carbon (No. 5) diminishes TABLE I THE EFFECT OF PHENYLALKYLAMINES ON VASOPRESSOR ACTION AND TOXICITY Compound No. Structure R Pressor Action*/ Toxicity Ref. Animal Relative Potency Animal Admin. mgm. /kgm. 1 CH2 cat 1000 14 2 CH(CH3) cat 1000 14 3 CH2CH2 cat 350-500 14 cat 183 101 dog 95 77 dog 100 mouse i v> LD50, 95t5Â£ 60 rabbit i. v. MLD, 60 45 rat i.p. LD, 23 48 rat oral LD, 50 48 4 CH2.CH2 CH2 cat 1471 101 dog 700 rat i. v. LD50, 50 38
TABLE I (cont. ) C om pound No. Structure R Fressor Action Toxicit â Ref. Animal Relative Potency Animal A.dmin mgm. /kgm. 5 CH2. CH(CH3) cat 425 101 dog 321 mouse i.p. ALD50, 120 60 dog 100-200 guinea pig s. c. LD3/5. 52 7 dog 250 rat i. v. LD50, 20 38 dog 237 74,77 rat s. c. MLD, 25 45 mouse a. c. LD50, 79.8 23 6 CH(CH3).CH2 cat 1015 1.01 dog 500 37 dog 600 rabbit i. v. LD50, 55 109 dog 350 mouse i. v. LD50, 46 i 1 60 dog 254 74 mouse i. v. ALD5o. 60-65 110 mouse s. c. LD50, 540 110 7 CH(C2H5) cat 800 101 dog weak rat s.c. MLD. 1000 45 rabbit s. c. MLD, 50 45 8 CH(CH3) CH(CH3) dog 800 rabbit i. v. LD50, 38 109 9 CH2CH(C2H5) cat 500 rat i.p. LD. 70 48 rat oral LD. 400 48 dog 275 77 10 C(CH3)2-CH2 dog 700 mouse i.p. ALD50, 50 60 11 CH2.C(CH3)2 dog 1000 60 dog 600 109 12 C(CH3)2.CH(CH3) dog 1000 mouse i.p. ALD50, 70 60 13 CH2 CH(C3H7) cat almost rat i.p. ALD, 70 48 inactive rat oral ALD, 400 48 14 CH(C2H5).CH(CH3) dog 1000 rabbit i. v. LD50, 38 109 15 CH(i-C3H7).CH(CH3) dog 1000 rabbit i. v. LD50* 30 109 3/ Response obtained after intravenous injection & i.p., intraperitoneal; i. v. , intravenous; s.c., subcutaneous injection Sj Values reported as the LD - lethal dose, MLD - minimum lethal dose, LD50 - lethal dose t the standard error which kills 50 per cent within 24 hours, ALD - approximate LD5g
76 vasopressor potency less than a similar substitution at the beta carbon (No. 6). Increasing the number of carbon atoms in the side chain to more than three (Nos. 8-15) causes a great reduction in potency except in the case of 3-phenylbutylamine (No. 9). As pointed out above, the optimum (1) (2) structure is N- C - C -phenyl and substitution reduces vasopressor potency in the following order: 1-methyl, 2-methyl 1-ethyl, 2 , 2-dimethyl, 1 - 1-dimethyl, 2, 2-dimethyl-1 , 1-dimethyl. (The designation of the position of the carbon atoms as C-l or C-2 will be used throughout this presentation). The greater effectiveness of compounds substituted by methyl at the first carbon may result from the central nervous system stimulation which these compounds are reported to produce?' ?7,109added to the peripheral cardiovascular effects. No such stimulation has been observed with derivatives substituted at the second carbon85, 109, 1 10. Substitution of the amine of these simple derivatives by a methyl group generally reduces pressor potency (Table II). Marsh?5,77 found p-phenylethylamine (No. 3) 1. 4 times more active TABLE II THE EFFECT OF PHENYLALKYLMETHYLAMINES ON VASOPRESSOR ACTION AND TOXICITY R-NHCH3 Compound No. Structure R Pressor Action^/ Toxicity Ref. Animal Relative Potency Animal Admin. mgm. /kgm. 16 CH2 CH2 cat. 300-500 14 dog 200 mouse i.p. ALD50, 190 60 dog 135-148 75 17 CH2 CH2. CH2 dog 250 rat s. c. LD50- 60 38 18 CH2.CH(CH3) cat 695 93 dog (d) 116 mouse i.p. ALD50, 70 65 (d, 1) 200 mouse i.p. ALD50. 70 65 dog (1) 272 mouse i.p. ALD50, 70 65 dog 365 74 rat i.p. MLD, 17 48 19 CH(CH3) CH2 dog 600 rabbit i. v. LD50, 65 109 dog 260 74 rabbit i. v. LD50, 72 + 1.7 110 mouse i. v. LD50, 60 + 3.4 110 rabbit 8. C. LD50, 205 + 15.9 110 rat s. C. LD50, 850 + 37 110 rat i.p. LD50, 165 + 9.2 110 20 CH(CH3)-CH(CH3) dog 1000 mouse i.p. ALD50, 70 60 21 C(CH3)2.CH2 dog 1000 mouse i.p. ALD50, HO 60 22 CH2 C(CH3)2 dog 1000 60 23 C(CH3)2.C(CH3)2 dog 1000 mouse i.p. ALD50, 90 60 See footnote, Table I, p. 75
77 than the corresponding NÂ»methyl analog (No. 16). Derivatives with four or five carbons in the side chain also show this reduction in potency with N-methyl substitution. Results obtained with p-phenylisopropylamine (amphetamine. No. 5) and its N-methyl analog (methamphetamine, No. 18) are somewhat variable. Data obtained with the cat^i '01 and dog7, 48, 74, 77 indicate less pressor action with the N-methyl derivative (No. 18). A careful evaluation of p-phenyl-n-propylamine (No. 6) and the N-methyl analog ('Vonedrine'. No. 19) by Warren et all 09 did not disclose any important difference in potency. This has been confirmed by Marsh?*. The toxicities of these phenylalkylamines, shown in Tables I and II, are relatively low. Increasing the size of the side chain apparently causes some increase in toxicity. Thus, p-phenyl- ethylamine is only about one-half as toxic as p-phenylisopropylamine by intravenous injection to rats. It should be noted also that intravenous injection into rabbits of the larger molecules (Nos. 7, 8, 14 and 15) indicated some increase in toxic action over that of p-phenylethylamine (No. 3). The N-methyl derivatives may be slightly less toxic than their primary amine analogs. The substitution of an alcoholic hydroxyl group at C-i of phenylalkylamines is generally unfavorable for vasopressor action (Table III). When compared in the same experiments. TABLE III THE EFFECT OF PHENYLAM1NOALKANOLS ON BLOOD PRESSURE AND TOXICITY Compound No. Structure X Y Pressor Action*/ Toxicity Ref. Animal Relative Potency Animal Admin. mgm. /kgm. 24 H H cat less active rabbit i.v.V MLD, A' 80 24 than No. 3 cat 300-500 14 cat 124. 5 25 rabbit i. v. ALD, 30-90 6 rat i. v. MLD. 140 96 25 CH3 H cat 60 101 cat 80 rabbit i. v. MLD, 75 24 dog 220 mouse i.p. ALDc,:.. 440 60 26 C2H5 H cat 2262 101 cat 1000 (approx. ) rabbit i. v. MLD, 50 24 27 C3H7 H dog none 47 cat depressor 101 28 C4H9 H cat depressor 101 29 C6H13 H cat depressor 101 30 H CH3 cat less active rabbit i. v. MLD, 100 24 than No. 24 dog 270 mouse i.p. ALD5o. 490 60
78 TABLE III (Cont. ) Compound No. Structure X Y Pressor Action^/ Toxicity Ref. Animal Relative Potency Animal Admin. mgm. /kgm. 31 CH3 CH3 cat (d, 1) 190 rabbit i. v. MIX>, 60 24 cat (1) 142 rabbit i. v. MLD, 60 24 cat (d) 420 rabbit i. v. MJ..D. 80 24 dog (c,1) 466 mouse i.p. ALD50, 275 60 (1 )rabbit i. v. LD50, 6013.2 110 (1 )rabbit s. c. LD50, 17519.2 110 (1 )mouse s. c. LD50, 600 t 55 1 10 (l)rat s . c. LD5o, 650+109 110 (1 )mouse s. c. LD50, 276. 9 23 32 C2H5 CH3 cat 1/6 activity rabbit i. v. MLD, 45 24 of No. 3 33 C3H7 CH3 cat depressor rabbit i. v. MLD, 35 24 34 H CH(CH3)2 dog depressor mouse i. v. ALD50, 180 66 35 H C4H9 cat depressor rabbit i. v. MLD. 50 24 36 CH3 C2Hj cat No. 31 rabbit i. v. MLD, 50 24 37 CH3 C3H7 cat depressor rabbit i. v. MLD, 50 24 38 CH3 CH(CH3)2 cat si. pressor rabbit i. v. MLD, 40-50 24 39 CH3 C4H9 cat depressor rabbit i. v. MLD, 15 24 40 CH3 C5H1 1 cat depressor rabbit i. v. MLD, 20 24 41 (CH3)2 H dog 1000 60 See footnote, Table I, p. 75 P-phenylethylamine (No. 3) is more pressor than 1 -phenyl-2-aminoethanol (No. 24) and N-methyl- P -phenylethylamine (No. 16) more active than 1 -phenyl-2-methylaminoethanol (No. 30)24, 60. This relationship is not clearly evident with the corresponding propyl derivatives. Tainter^^ found l-phenyl-2-amino-l-propanol (No.. 25) distinctly more pressor than p-phenylisopropylamine in cats. Similar results have been obtained with the dog^O However, results obtained with the corresponding methylamines are variable and not in agreement with the above findings for the primary amines. Results obtained with cats suggest higher activity for 1 -phenyl-2-methylamino- 1-propanol (No. 31), this relationship being reversed in experiments on dogsZ4, 60, 65, 93 Little or no pressor action was obtained with compounds in which the side chain contained more than three carbon atoms. As shown in Table III, most of these higher homologs lowered blood pressure. A comparison of the most pressor compounds in Tables I-III suggest that the alcoholic hydroxyl at C-2 diminishes toxicity. The toxicity of p-phenylethylamine (No. 3) is probably slightly greater than 1-phenyl-2-aminoethanol (No. 24); p-phenylisopropylamine (No. 5) more than 1 -phenyl -2-amino- I -propanol (No. 25). Increasing the size of the alkanol side chain increases toxicity, as previously pointed out for the phenylalkylamines. It is interesting to compare the activities and toxicities of the optical isomers of Nos. 18 and 31. In the case of
No. 18, greatest vasopressor activity is obtained with the d-isomer; with No. 31, with the 1- isomer. This difference may result from the marked stimulating action on the central nervous system (possibly the vasomotor centers) observed with the d-isomer of No. 18 (see Table XXV, p. 108) However, this difference in physiological activity between the d- and 1.isomers did not significantly influence acute toxicity inasmuch as there was no important difference between the optical isomers and the racemic mixture. Substitution of the phenyl ring at the 4-position with an hydroxyl increases pressor action of the most pressor derivatives (Table IV). In order of increasing pressor potency, we find TABLE IV THE EFFECT OF 4-HYDROXYPHENYLALKYLAMINES ON BLOOD PRESSURE AND TOXICITY H0i .CH2 X NHY Compound No. Structure X Y Pressor Action^/ Toxicity Ref. Animal Relative Potency Animal Admin. mgm./kgm. 42 CH2 H cat 105 14 cat 70 13 dog 68 mouse i . v. LD50, 260 t 20 60 dog 50-100 guinea pig s. c. LD3/5, 2088 7 mouse s . c. MLD, 2750 12 43 CH2 CH3 cat 140 13 dog 68 mouse i.p. ALD50, 760 60 44 CH(CH3) H dog 50-100 guinea pig s. c. LD4/5, 184 7 dog 59 60 dog 100 rat i. v. LD50, 100 38 cat 124 25 45 CH(CH3) CH3 dog 250 rat i. v. LD50, 100 38 46 CH2 CH2 H dog 1750 rat i. v. LD5o. 170 38 47 CH2-CH2 CH3 dog 750 rat i. v. LD5o, 170 38 See footnote, Table I, p. 75 1 -phenyl-2-aminoethanol (No. 24) < p-phenylethylamine (No. 3) < p-(4-hydroxyphenyl)ethylamine (No. 42). The N-methyl analog of the last compound (No. 43) is equal to or slightly Less pressor than the primary amine The introduction at C-2 of an alcoholic hydroxyl reduces pressor potency (Table V). Thus, 1 -(4-hydroxyphenyl)-2-aminoethanol (No. 48) is only one-half to one- fifth as pressor as the corresponding ethane derivative.
80 TABLE V THE EFFECT OF 4-HYDROXYPHENYLAMINOALKANOLS ON BLOOD PRESSURE AND TOXICITY CH- CHX- NHY OH Com- pound No. Structure X Y Effect on Blood Pressure^ Toxicity Ref. Animal Relative Potency Animal Admin mgm. /kgm. 48 H H dog E,^ 200 mouse i.p. ALD50, 600 66 dog E, 100 14 cat E, 500 78 49 H CH3 dog E, 440 mouse i.p. M.DSQ. 1000 66 dog E, 250 mouse i. v. -DS0. 270 t 12 60 cat E, 116 104 cat E, 60-100 1) mouse s. c. ULD. 700-800 58 d) mouse s. c. MLD. 1500 58 50 H C2H5 dog I, 600 mouse i.p. ALD5o. 600 66 dog I. 1000Â£/ 78 51 H CH(CH3)2 dog I, 350 mouse i.p. ALD50, 370 66 dog I, 200^ 78 mouse i. v. -D50, 144 t 10 60 52 H C3H7 dog I. 1000S/ mouse i. p. ALD50, 300 66 53 H C4Hg dog I, lOOOtf mouse i.p. ALD50. ISO 66 dog I, 1000Â£/ 78 54 H CH(CH3)-C2H5 dog I, 500 67 55 H C(CH3)3 dog I. 350 mouse i.p. ALD50, 250 66 dog I, 350 78 56 H CH2.CH(CH3)-CH i dog I. very weak mouse i.p. ALD50. 220 66 57 CH3 H cat E. 108 rabbit i. v. MLD, 130 24 cat E, 67 100 58 CH3 CH3 dog E, 100-200 84 59 C2H5 H dog E, 1000 67 See footnote. Table I, p. 75 E. Multiples of the effective pressor dose of epinephrine I, Multiples of the effective depressor dose of 'Isuprel' Approximately
81 In experiments on the dog, N-alkyl substitution of 1 -(4-hydroxyphenyl)-2-aminoethanol (No. 48) results in depressor action when the N-alkyl substituent is larger than methyl. This depressor action has been expressed as multiples of the effective dose of 'Isuprel' (No. 103). The N-isopropyl (No. 51) and N-.t. -butyl (No. 55) derivatives were the most potent depressor agents. Derivatives in which the N-alkyl group is propyl, butyl or isobutyl have low activity. This suggests that the structural requirements favorable for depressor action are -NH-C- in which the hydrogen atoms of this methyl group are replaced by one (No. 50), two (No. 51) or three (No. 55) H methyl groups64, 66, 67. Derivative No. 54 in which the N-alkyl group is -NH. C. C2H5 was found CH3 to be less potent than Nos. 51 and 55. When there is no methyl substitution, as indicated above, or when larger groups are substituted (Nos. 52, 53 and 56), depressor potency is greatly reduced or abolished. The alcoholic hydroxyl at C-2 is important for this action66. This will be discussed in a subsequent portion. Increase in the size of the side chain to propanol (Nos. 57 and 58) does not influence pressor potency; an increase to butanol (No. 59) causes a great reduction. Hydroxyl substitution of the phenyl ring at the 3-position appears to influence pressor action of these ethane derivatives to no greater extent than does substitution at the 4-position (Tables IV and VI). A comparison of the pressor potencies of f3-phenylethylamine (No. 3) with the TABLE VI THE EFFECT OF 3-HYDROXYPHENYLALKYLAMINES ON BLOOD PRESSURE AND TOXICITY HO/ CH2-X NHY Compound No. Structure X Y Pressor Action Toxicity Ref. Animal Relative Animal Admin. mgm./kgm. Potency 60 CH2 H cat 100 14 61 CH(CH3) H dog 300 rat i. v. LD50, 70 38 62 CH(CH3) CH3 dog 125 rat i. v. LD50, 60 38 63 CH(CHa) CH2.C6H5 dog 2000 rat i. v. LD50, 35 38 64 CH2- CH2 H dog 300 rat i. v. LD50, 90 38 65 CH2-CH2 CH3 dog 250 rat i. v. LD50, 90 38 66 CH2. CH2 CH2. C6H5 dog 2000 rat i. v. LD50, 45 38 67 CH2 CH(CH3)2 dog depressor See footnote, Table I, p. 75
corresponding 3- (No. 60) and 4-hydroxyphenyl (No. 42) analogs suggest that the three compounds have activities of a similar order of magnitude. An increase in the size of the side chain to propyl and alkyl substitution of the amino group reduces pressor potency. Both P-(3-hydroxy- phenyl)isopropylamine (No. 61) and \-(3-hydroxyphenyl)propylamine (No. 65) have been reported to be less effective than p-(3-hydroxyphenyl)ethylamine (No. 60). A comparison of toxicity data in Tables IV and VI suggest that the 3-hydroxyphenyl derivatives are more toxic than the corresponding 4-hydroxy analogs. A direct comparison of acute intravenous toxicity in the rat of P-(4-hydroxyphenyl)isopropylamine (No. 44) with P-(3- hydroxyphenyl)isopropylamine (No. 61) suggests that the latter is approximately one-third more toxic3S Similarly with the v-phenylpropylamines (Nos. 46 and 64), the 3-hydroxyphenyl compound is about two times more toxic than the 4-hydroxy analog. The addition of an alcoholic hydroxyl at C-2 diminishes toxicity. This is illustrated by compound Nos. 43 (Table IV) and 49 (Table V). The ethanol derivative is approximately one-third less toxic. Unfortunately other toxicity data in Table V cannot be used for direct comparison with that in Table IV, but indicates toxicities of a relatively low order of magnitude. There is a marked difference in the effect of the alcoholic hydroxyl at C-2, depending upon whether the phenolic hydroxyl is at the 3- or 4-position on the ring. A comparison of the pressor potency of 1-(3-hydroxyphenyl).-2-aminoethanol (No. 68) with that of the 4-hydroxyphenyl analog (No. 48) reveals a five to ten-fold greater potency for the former (Table VII). The N-methyl TABLE VII THE EFFECT OF 3-HYDROXYPHENYLAMINOALKANOLS ON BLOOD PRESSURE AND TOXICITY CH-CHX NHY \==/ OH Compound Structure X Y Effect on Blood Pressure Toxicity Ref. No. Animal Relative Potency Animal Admin. mgm. /kgm. 68 H H dog E. 15-20 mouse i.p. ALD5o, 370-420 60 rabbit i. v. ALD50, 5-10 60 69 H CH3 cat (d,l) E. 15 mouse 1000 59 cat (d.l) E. 5.6 100 cat (1) E, 2. 3 25 dog (1) E. 7 mouse i.p. ALD5o, 14o 65 dog (d, 1) E. 12 mouse i.p. ALD5o. 420 65 dog (d) E. 77 65 1) rabbit i. v. LD50, 0.5 tO. 15 110 ;i )rabbit s. c. LD5o. 22t2.2 110 l)rat s. c. LD50, 27 + 2.9 110 l)mouse s. c. LD50, 2214. 3 110 70 H CH(CH3); dog I, 500 mouse i.p. ALD5o, 32o 66 71 CH3 H cat E, 9.8 25 72 CH3 CH3 cat (1) E, 107.7 25 73 CH3 CH(CH3); dog I, 1000 67
83 derivative (No. 69) is probably not significantly more pressor than the primary amine (No. 68). The difference in potency between the primary and secondary amine, when the phenolic hydroxyl is in the 4-position (Nos. 48 and 49), is somewhat more definite. Results obtained in this laboratory"" indicate a definite reduction in activity with N-methyl substitution. The N-isopropyl analog of No. 68 (No. 70) is distinctly vasodepressor, although less potent than 'Isuprel'. Lengthening of the side chain reduces this activity. These data indicate that the effect of the hydroxyl at C-2 and of N-methyl substitution is influenced by the presence of a phenolic hydroxyl in the 3-position. In its absence these substitutions either are without effect or diminish pressor potency. The increase in pressor activity of the 3-hydroxyphenylalkanolamines is associated with some increase in toxicity. Hydroxy substitution of the ring at the 3- and 4- or 3-, 4- and 5-positions (Nos. 76 and 77) may increase activity somewhat but not enough to change the order of magnitude (Table VIII). The TABLE VIII THE EFFECT OF RING SUBSTITUTION OF p-PHENYLETHYLAMINE ON VASOPRESSOR ACTION CH2 CH2NHY Compound No. Structure 43 2 Y Pressor Action^/ Reference Animal Relative Potency 3 H H H H cat dog 183 111-116 75 16 H H H CH3 dog 135-148 75 42 OH H H H dog dog cat 68 53-66 100 60 75 75 74 H OH H H cat 100 14 75 H H OH H cat 500 14 76 OH OH H H cat 50 57 14 60 dog 77 OH OH (5-OH) H dog 50 40 78 OH OH OH H cat 100 14 79 F H H H dog cat 74-80 120 75 75 80 F H H CH3 dog 97-100 220 75 75 cat 81 Cl H H H cat 368 98 82 NO2 H H H cat 823 98 83 CH3 H H H cat equals No. 3 43 84 C2H5 H H H cat No. 3 43
84 TABLE VIII (Cont. ) Compound Structure 4 3 2 Y Pressor Action^/ Reference No. Animal Relative Potency 85 CH3 H H CH3 cat equals No. 3 43 86 H CH3 H CH3 cat equals No. 3 43 87 H H CH3 CH3 cat one -half as active as No. 3 43 88 NH2 H H CH3 dog one -fifth as active as No. 3 18 See footnote, Table I, p. 75 2, 3, 4-trihydroxy substituted compound (No. 78) has approximately the same activity as the monosubstituted compounds, Nos'. 42 and 60. The P-(4-fluorophenyl)ethylamine derivatives (Nos. 79 and 80) are approximately equal in activity to the unsubstituted compounds (Nos. 3 and 16). The activity of p*-(4-chlorophenyl)ethylamine (No. 81) appears to be less than that of the corresponding fluoro-derivative. The 4-nitrophenyl analog is weak. Substitution of the ring with a methyl or ethyl group in the 4-position (Nos. 83-85) does not greatly influence pressor potency. Similarly, the 2- and 3-methyl substituted phenylethylamines (Nos. 86 and 87) have pressor activities comparable to that of the unsubstituted compounds. The 4-amino derivative (No. 88) appears to be distinctly less active than the corresponding unsubstituted compound (No. 16). The alcoholic hydroxyl at C-2 greatly increases pressor potency when the phenyl ring is substituted by an hydroxyl at the 3-position (see above) or by 3, 4-dihydroxy substitution (No. 90, arterenol, norepinephrine) but is ineffective when the hydroxyls are substituted at the 2,4- (No. 91) or Z. 5-positions (No. 94). The 2, 3, 4-trihydroxyphenyl derivative (No. 92) is depressor and the 3, 4, 5-trihydroxy derivative is inactive (Table IX). Maximum pressor activity is obtained TABLE IX THE EFFECT OF RING SUBSTITUTION OF 1 -PHENYL-2-AMINOETHANOL ON VASOPRESSOR ACTION AND TOXICITY OH Compound No. Structure 432 Pressor Action?/ Toxicity Ref. Animal Relative Potency Animal Admin. mgm. /kgm. 48 OH H H dog 200 mouse i.p. ALD50, 600 45 89 H OH H dog 20-40 mouse i.p. ALD50, 370-420 60
85 TABLE IX (Cont. ) Compound No. Pressor Action*" Toxicity Ref 4 32 Animal Relative Potency Animal Admin mgm. /kgm. 90 OH OH H cat (d.l) 1.5 14 cat (d, 1) 1.2 99 cat (d.l) 0.5 25 dog (1) 0.63 71 dog (d) 27.5 71 (1) rat i. v. LD5o, 0.1 t0. 01 50 (d, 1) rat i. v. LD50, 0.13Â±0.02 50 (d) rat i. v. LD50, 1.4 +0. 14 50 (1) mouse i. v. LD50. 5 t 1 50 (d. 1) mouse i. v. LD50. 7.5 +2 50 (d) mouse i. v. LD50, 60 120 50 91 OH H OH very weak 17 92 OH OH OH rabbit depressor 70 93 OH OH (5 -OH) rabbit inactive 70 94 (5 -OH) H OH rabbit weak 70 See footnote. Table I, p. 75 with the primary amine (No. 90, nor-epinephrine) or the N-methyl homolog (No. 95, epinephrine). The N-ethyl derivative (No. 96) is both pressor and depressor. Intravenous injection causes an initial transient rise in blood pressure followed by a sharp fall. This diphasic response has also been observed with the N-propyl derivative (No. 97). The N-butyl and -amyl derivatives (Nos. 98 and 99) are depressor. The N- isopropyl compound (No. 100, isopropylarterenol, 'Isuprel', 'Aleudrine') is a potent vasodepressor substance and, for the purpose of this review, activities of other depressor amines are expressed as multiples of the effective dose of this drug. The N- sec. -butyl (No. 101) analog is somewhat less potent and the N-t^. -butyl (No. 102) analog more potent than 'Isuprel'. The N-isobutyl (No. 103) and -cyclopentyl (No. 104) analogs are one-fifth to one-ninth as depressor as 'Isuprel'. The substitution of larger N-alkyl groups (Nos. 105-107) causes a marked reduction in depressor potency. Epinephrine has a very high toxicity and is the most toxic amine tabulated in this review. The primary amine (arterenol) and N-ethylarterenol are slightly less toxic than epinephrine. The substitution of larger N-alkyl groups results in a distinct reduction in toxicity. 'Isuprel' is approximately thirty times less toxic than epinephrine. An examination of these data also shows that the toxicity of the 1-isomers of both arterenol and epinephrine are distinctly more toxic than the d-isomers or the racemic mixtures. Similarly, pressor action results largely from the 1-isomers inasmuch as the potency of the d-isomer is very small. This high toxicity appears to be closely related to the high excitatory sympathomimetic (vasopressor) actions of these drugs. The effective dose of 'Isuprel' is somewhat less than that for epinephrine"4 but, by comparison, has a very low toxicity. The inhibitory sympathomimetic action, represented by this response, does not appear to be closely related to toxicity. An examination of the toxicity of compound Nos. 48, 89 and 90 (Table IX) shows an increase with hydroxy substitution of the ring in the order 4-hydroxy < 3-hydroxy < 3, 4-dihydroxy. The alcoholic hydroxyl at C-2 increases both pressor action and toxicity. However, with a single hydroxyl at the 4-position on the ring both vaso- pressor action and toxicity are diminished by the hydroxyl at C-2 These findings suggest that the increase in toxicity is directly related to the increase in pressor action.
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88 Significant vasodepressor action is observed with 1 -phenyl-2-isopropylaminoethanol (No. 34) but is absent with N-isopropyl - (i-phenethy Iamine66. Substitution of the phenyl ring of No. 34 by an hydroxyl at either the 3- or 4-position increases this depressor action, the increases observed being of a similar order of magnitude. Maximum action is obtained when both hydroxyls are present ('Isuprel') and absent when the alcoholic hydroxyl is removed from C-2. "* The hydroxyl group at C-2 appears to be most important for vasodepressor action. It would appear that the 3-hydroxy group on the phenyl ring is the key structure for vaso- pressor action and that the alcoholic hydroxyl at C-2 is similarly the key structure for vasode- pressor action. Other substitutions are important insofar as they modify these actions. This is further illustrated by the data shown in Table XI. When the hydroxyl at C-2 of 'Isuprel1 is TABLE XI THE EFFECT OF THE ALCOHOLIC HYDROXYL ON VASOPRESSOR ACTION AND TOXICITY ,o CHCH2 NHY "om- No. Structure 4 3 X Y Pressor Action*f Toxicity Ref. Animal Relative Potency Animal Admin mgm. /kgm. 3 H H H H cat 183 101 dog 100 mouse i. v. LD50, 9515 60 108 OH H OH cat 14 109 (2, 5-dihydroxy) O H cat inactive 17 110 OH OH OH cat 23 14 1 11 OH OH O CH3 cat 23 14 dog 52 mouse i.p. LD50, 902 t 25 64 112 OH OH O C2H5 cat 15 14 113 OH OH O C3H7 cat 140 14 1 14 OH OH O CH(CH3)2 dog >1000 mouse i.p. LD50. 470t 15.6 64 42 OH H H H cat 70-105 13 14 dog 68 mouse i. v. LD50, 280 t2O 60 76 OH OH H H cat 50 14 200 (2, 5-dimethoxy) H H dog + 50 mm. Hg at mouse i.p. LD50. 161 49 0. 0025 mM/kgm 200a (2, 5-dimethoxy) H CH3 dog + 50 mm. Hg at mouse i. p. LJ^SO. 124 49 0. 002 mM/kgm. 115 OH OH H CH3 cat 7 14 dog 6. 5 mouse i. v. LD50, 770172 64 116 OH OH H C2H5 cat 23 14 . J
89 TABLE XI (Cont. ) Com- pound No. Structure 43 X Y Pressor Action^/ Toxicitv Ref. Animal Relative Potency Animal Admin. mgm. ,/kgm. 117 OH OH H CH(CH3)2 dog pressor or depressor mouse i.p. LD50, 500t 22 64 90 OH OH OH H cat dog (d,l) 0. 5-1. 5 (1) 0.63 14, 25, 99 71 95 OH OH OH CH3 1 (See Table X) 95a OH NH2 OH CH3 cat weak 32a 118 OH OH OH C2H5 depressor (See Table X) 206 (2,5-dimethoxy)OH H dog + 50 mm. Hg at 0. 001 mM/kgm. i.p. LD50, 131 49 206a (2,5-dimethoxy)OH CH3 dog + 50 mm. Hg at 0. 0005 mM/kgm i.p. LD50, 94 49 See footnote. Table I, p. 75 replaced by =O (No. 114), the resultant compound is not depressor but is a weak pressor agent. The corresponding primary amine (No. 110) and the N-methyl analog (No. Ill) are potent pressor drugs. All of the ketone derivatives shown in this table, except the 2, 5-dihydroxyphenyl deriva- tive (No. 109), have some pressor action. Similarly, removal of the hydroxyl at C-2 to give N- isopropyl -p-(3, 4-dihydroxyphenyl)ethylamine (No. 117) may cause a rise in blood pressure. The corresponding primary amine (No. 76) and the N-methyl analog (No. 115, 'Epinine') are potent pressor agents. The replacement of the phenolic hydroxyl at the 3-position on the phenyl ring by a methyl group (No. M9, Table XII) causes a great reduction in pressor potency (compare with No. 68). TABLE XII THE EFFECT OF RING SUBSTITUTION OF 1 -PHENYL-2 -AMINOPROPANOL AND l -PHENYL-2 -METHYLAMINOPROPANOL ON VASOPRESSOR ACTION AND TOXICITY V-V* f /9H - CH CH(CH3)-NHY Compound No. Structure 43 2 Y Pressor Action*/ Toxicity Ref. Animal Relative Animal Admin. mgm. /kgm. Potency 25 H H H H cat 60-80 rabbit mouse i. v. i.p. MLD, 75 ALD5o. 440 2, 13 60 119 H CH3 H H cat 168 101
90 TABLE XII (Cont. ) Compounc No. Structure 4 3 2 Y Fressor Action^/ Toxicity Ref. Animal Relative Potency Animal Admin. mgm./kgm 120 OH CH3 H H cat 288 101 121 CH3 OH H H cat 151 101 122 CH3O H H H 1/2 as active as No. 25 rabbit i. v. MLD, 35 47, 101 123 H H CH3O H 60-80 47, 101 cat 226 101 124 CH3O H CH3O H cat depressor 101 125 CH3O CH3O (5-CH3O) H cat very weak 101 126 (5-CH3O) H CH30 H dog + 50 mm. Hg at 0.0006 mM/kgm. mouse i.p. LD50. 92 49 126a (5-CH3O) H CH3O CH3 dog + 50 mm. Hg at 0.001 mM/kgm. mouse i.p. LD50, 96 49 127 NH2 H H CH3 cat 153 101 127a OH NH2 H CH3 cat very weak 32a 128 OH OH NH2 CH3 very weak 72 129 Cl H H H cat 248 101 See Footnote, Table I, p. 75 With a 3-methyl group present, the subsequent addition of a 4-hydroxy group (No. 120) causes a further reduction in potency. When these positions are reversed (No. 121), the resultant compound is almost twice as active with a corresponding increase in toxicity. The effect of methoxy substitution on the phenyl ring is variable. The 2-methoxy, 4-methoxy and 2,5- dimethoxy derivatives equal the pressor activity of the unsubstituted compound (No. 25) or are one-half as active '. "" . The 2, 4-dimethoxy and 3, 4, 5-trimethoxy analogs are either very weak or inactive^1 101 Amino substitution at the 4-position (No. 127) decreases action and the 2-amino-3, 4-dihydroxy analog (No. 128) is almost inactive. The substitution of chlorine at the 4-position on the ring reduces pressor potency to about one-fourth that of the unsubstituted compound. Increase in the length of the side chain by substitution at C-l reduces pressor potency (Table XIII), particularly when the substituent is as large as ethyl (No. 131). Substitution of the amine by a methyl (No. 132) or larger alkyl group results in compounds with depressor action.
91 TABLE XIII THE EFFECT OF VARYING THE LENGTH OF THE SIDE CHAIN OF 1 -(3,4-DIHYDROXY - PHENYL)-2-AMINOALKANOLS ON BLOOD PRESSURE ACTION AND TOXICITY CH. CHX. NHY OH Compounc No. Structure X Y Effect on Blood Pressure*/ Toxicity Ref. Animal Relative Potency Animal| Admin. mgm. /kgm. 90 H H cat (d,l) E.J* 0.5-1.5 (d,l) E, 1.35 (See 1 .able IX) 14,25, 99 64 dog 130 CH3 H dog cat E, 2 E. 12 E, 3.3 rat i. v. LD50. 8 84 99 105 131 C2H5 H cat dog I, 300 E.I. 200,200 mouse i. v. LD50. 117 + 1 101 63, 102 95 H CH3 E. 1 (See Table X) 132 CH3 CH3 dog I 84 100 H CH(CH3)2 I. 1 (See Table X) 133 CH3 CH(CH3)2 dog I. 7 mouse i. v. ALD50,42 60 134 C2H5 CH(CH3)2 dog I, 16 mouse i. v. LD50, 57t2 63 104 H cyclopentyl dog I. 5 mouse i. v. (See 1 ALDsn.53 'able X) 67 135 C2H5 cyclopentyl dog I, 14 mouse i. v. LD50. 83t7 63 107 H cyclohexyl dog I, 31 mouse (See 1 i. v. .able X) ALD50.67 67 136 CH3 cyclohexyl dog I, 440 mouse i. v. ALD50.47 60 137 C2HÂ§ cyclohexyl dog I, 500 mouse i. v. LDSO, 83+4 63 See footnote, Table I, p. 75 See footnote, Table V, p. 80 Depressor action is also dimished by lengthening of the side chain. Thus with the N-isopropyl analogs, the effect on pressor potency of substitution at C-l is H > CH3 > C2H5 (Nos. 100, 133, 134). Similar results were obtained with the N-cyclopentyl and N-cyclohexyl derivatives. These data suggest that a two carbon side chain is optimum for both pressor and depressor action. Toxicity of pressor compounds diminishes along with the reduction in pressor potency. This is illustrated by the primary amines in Table XIII (Nos. 90, 130 and 131). Increase in the length of the side chain by substitution at C-l reduces both pressor action and toxicity. The butanol derivative (No. 131) has about 1/200 - 1/300 the pressor action and about 1/15 the
92 toxicity of the primary amine (No. 90). All of the depressor compounds have relatively low toxicities. There does not appear to be any clear correlation between the size of the side chain and toxicity with these compounds. Dialkyl substitution of the amino group (Table XIV) greatly diminishes or abolishes pressor TABLE XIV THE EFFECT OF DIALKYL SUBSTITUTION OF THE AMINE GROUP OF VARIOUS PHENYLALKYLAMINES ON VASOPRESSOR ACTION Compound No. Structure 4 3 R X Y Pressor Action^/ Ref. Animal Relative Potency 138 H H H CH2 (CH3)2 dog weak 83 139 H H H CH2 (C2H5)2 dog variable 83 140 H H H CH2 (C3H7)2 weak 20 141 H H OH CH(CH3) (CH3)2 cat weak 24 142 H H OH CH(CH3) CH3, C2H5 dog (1) very weak 16 143 H H OH CH(CH3) (C2H5)2 cat very weak 57 144 OH H H CH2 (CH3)2 cat variable 101 145 NH2 H H CH2 (CH3)2 dog >No. 134 18 146 OH H OH CH2 (CH3)2 dog 1000 67 147 OH H OH CH2 (C2H5)2 dog >2000 67 148 OH H OH CH2 [CH(CH3)2]2 dog inactive 67 149 OH OH OH CH2 CH3 cat cat dog cat dog 25 10-20 25-35 25 40 39 88 90 108 108 ^ See footnote, Table I, p. 75 action. Only the N-dimethyl analog of arterenol (No. 149) possesses significant vasopressor action. The N-diisopropyl analog (No. 148) of the active vasodepressor compound, 1 -(4-hydroxy- phenyl)-2-isopropylaminoethanol, is inactive. Toxicity data have been available to the writer for only a few compounds. One of these, No. 149, has been reported to have an intravenous lethal dose in rabbits of 40 mgm. /kgm. and a subcutaneous lethal dose in mice of 250 mgm. /kgm. The corresponding secondary amine, epinephrine, is approximately 100-200 times more toxic.
93 The effect of hydrogenation of the phenyl ring on vasupressor action is shown in Table XV. TABLE XV THE EFFECT OF HYDROGENATION OF THE PHENYL RING OF VARIOUS SYMPATHOMIMETIC AMINES ON BLOOD PRESSURE AND TOXICITY CH.X.NHY R Compound No. Structure 4 R X Y Pre sor Action^ Toxicity Ref. Anima Relative Potency Animal Admin. mgm. /kgm. 150 H H CH2 H cat weak mouse i.p. ALD5o, 360 41 dog 565 mouse i.p. ALD50, 150 60 274 74 151 H H CH2 CH3 dog 324 mouse i.p. ALD50, 125 61 dog 230 74 152 H H CH2 C2H5 dog 350 mouse i.p. ALD50, 100 61 153 H CH3 CH2 H dog 539 mouse i.p. ALD50, 90 60 dog 516 74 154 H CH3 CH2 CH3 dog 312 mouse i.p. ALD50, 100 60 dog 435 74 155 H OH CH2 CH3 dog 1000 mouse i.p. ALD50, 240 60 156 OH OH CH2 CH3 dog >1000 mouse i.p. ALD5o. 66o 60 157 OH OH CH2 CH(CH3)2 dog >2000 60 158 H H CH(CH3) H dog 475 92 dog 225 mouse i.p. ALD50, 60 60 dog 333 74 cat 200-400 mouse i.p. ALD50, 60 41 159 H H CH(CH3) CH3 dog d,l) 290 mouse i.p. ALD50, 70 65 d) 400 mouse l-Ps ALD5o- 70 65 1) 160 mouse i.p. ALD50, 70 65 dog d, 1) 479 74 dog d,l) 710 92 160 H H CH2-CH2 H cat 200-400 mouse i.p. ALD50, 120 41 161 H H CH2.CH2 CH3 dog 250 mouse i. p. ALD5o. 125 61 See footnote, Table I, p. 75
94 Examination of these data discloses a marked reduction in pressor potency in most instances. Thus, p-cyclohexylethylamine (No. 150) is one-third to one-fifth as potent as the corresponding phenyl analog. A comparison of the activity of the isomers of N-methylcyclohexylisopropylamine (No. 159) with the corresponding phenyl analogs is of interest. The 1-isomer of the cyclohexyl derivative is 2. 5 times more active than the d-isomer, whereas with the phenyl analog, this relationship is reversed. Although the racemic cyclohexyl derivative is weaker than the corresponding phenyl compound, the activity ratio between the optical isomers of the two compounds is approximately the same, indicating that hydrogenation reduces activity of both isomers to about the same extent but causes a change in the sign of optical rotation. As with the phenyl compounds, both the 4-hydroxyl group on the ring and an alcoholic hydroxyl at C-2 diminish pressor potency. The cyclohexyl analogs of active vasodepressor compounds are weak pressor agents. Saturation of the ring is unfavorable for vasodepressor action. The effect on toxicity of hydrogenating the phenyl ring is inconstant. The toxicity of cyclohexylisopropylamine is identical with that of the phenyl analog; N-methyl-p-cyclohexylethyl- amine is about four-fifths as toxic as the phenyl analog. The addition of a 4-hydroxyl and/or an alcoholic hydroxyl at C-2 reduces toxicity (see Nos. 151 and 156). In this respect, they resemble the corresponding phenyl analogs (see Nos. 16 and 49). Reduction in the size of the ring from cyclohexyl to cyclopentyl may cause some further reduction in pressor potency (Table XVI). A comparison of the pressor potency of p-cyc lope ntyl- TABLE XVI THE EFFECT OF CYCLOPENTYLALKYLAMINES ON VASOPRESSOR ACTION AND TOXICITY . CH2. X. NHY Compound No. Pressor Action* Toxicity Ref. X Y Animal Relative Potency Animal Admin. mgm. /kgm. 162 CH2 H dog 710 92 163 CH2 CH3 dog 300 mouse i.p. ALJD5o, 125 61 164 CH2 C2H5 dog inactive mouse i.p. ALD50, 115 61 165 CH(CH3) H dog 350 92 166 CH(CH3) CH3 dog 190 mouse mouse i. v. oral LD50, 41.6 + 1. 5 UD50, T68.7 t 19.7 92 92 167 CH(CH3) C2H5 dog 475 92 See footnote, Table I, p. 75 ethylamine (No. 162) with that of the cyclohexyl analog (No. 150) reveals a reduction in potency of thirty to sixty per cent. By contrast with the phenyl series, N-methylation of both the cyclopentyl and cyclohexyl derivatives causes some increase in pressor action over that of the primary amine. This is particularly marked with the cycloalkylisopropylamines (Nos. 158 and 195; Nos. 165 and 166). Swanson and Chen^Z found cyclopentylisopropylamine (Nos. 165) and N-methylcyclopentyliso-
propylamine (No. 166) distinctly more pressor than the corresponding cyclohexyl derivatives (Nos. 158 and 159). Both cyclohexyl- and cyclopentylalkylamines are of comparable toxicity. The vasopressor action of several aliphatic amines is shown in Table XVII. Barger and TABLE XVII THE EFFECT OF ALIPHATIC AMINES ON VASOPRESSOR ACTION Pressor Action^ Ref. Compound No. Structure Animal Relative Potency 168 1 -aminobutane cat weak 14 cat depressor 101 169 1 -aminopentane dog 4800 91 cat 581 101 170 1 -amino- 3-methylbutane dog 3500 91 cat variable 101 171 2 -aminopentane dog 2500 91 172 1 -aminohexane dog 1300 91 dog 525 76 dog 500 69 173 1 -methylaminohexane dog 400 69 174 2 -aminohexane dog 1100 91 dog 455 76 175 1 -aminoheptane dog 590 76 dog 3600 91 176 2 -aminoheptane dog (d,l) 324 52,91, 94 (1) 456 94 (d) 237 94 (d,l) 222 76 177 1 -amino-3-methylhexane dog 385 76 178 2 -amino-2-methylhexane dog inactive 76 179 2 -amino-3-methylhexane dog 900 76 180 2-amino-4-methylhexane dog 227 76 dog 280 91 181 2-amino-5-methylhexane dog 286 76 182 2-methylaminoheptene dog < No. 176 3 183 3 -aminoheptane dog 2000 76 184 4 -aminoheptane dog 2500 76
TABLE XVII (Cont. ) Compound No. Structure Pressor Action3/ Reference Animal Relative Potency 185 1 -aminooctane dog inactive 91 186 2-aminooctane dog 1970 91 201 2 -amino-2-methy 1 he plane dog 263 78a 202 2-amino-3-methylheptane dog 710 78a 203 2-amino-4-methylheptane dog 590 78a 204 2-amino-5-methylheptane dog 400 78a 205 2 -amino-6 -methylheptane dog 256 78a */ See footnote, Table I, p. 75 Dale'* and Tainter"" have shown that there is little or no action on blood pressure with derivatives smaller than 1 -aminobutane (No. 168). There is a progressive increase inactivity as the length of the chain is increased to six or seven carbon atoms. Greatest vasopressor potency was obtained with 2-amino-4-methylhexane (No. 180) and 2-aminoheptane (No. 176). Further increase in size is not favorable. Thus, 2-aminooctane (No. 186) is much weaker than 2-aminoheptane and '.-aminooctane (No. 185) is inactive. Swanson and Chen1?' have also reported that introduction of a double bond into the aliphatic chain decreases potency, 2-aminohexene, 2-amino-5-methylhexene and 2-amino-6-methylheptene being distinctly less pressor than their saturated analogs. Swanson, Steldt and Chen'4 have examined the optical isomers of 2-amino- heptane. They found the d-isomer to be two times more active than the 1-isomer. In this respect. 2-aminoheptane resembles phenylisopropylamine and the N-methyl analog. Toxicity data are not presently available for most of the compounds described in Table XVII. Warren and Werner' 'O have described the toxicity of 2-aminoheptane. They have reported the following data (mgm./kgm. ): rabbit, i. v.', 22 Â± 14; i.m. , 85 t 5. 7; s. c. , 130 + 14.4; rat, i.p. , 34 Â± 2.2; s. c.,, 135 t 6. 1 to 160 t 13. 0 (light ?nd heavy animals respectively); mice, s. c. , 115 t 11.6. Miscellaneous compounds, evaluated for vasopressor action, are shown in Table XVIII. The thiophene derivatives (Nos. 187-189) have approximately the .same potencies as the corresponding phenyl analogs. Similarly, the toxicities are approximately equal to those of the phenyl analogs (Nos. 5 and 6). Other compounds shown are variable or depressor in action and probably do not have true sympathomimetic action. Many amines, when injected intravenously in doses of 0. 5-2. 0 mgm./kgm. , will cause similar variable response*.
TABLE XVIII THE EFFECT OF THIENYL- AND FURYLALKYLAMINES ON VASOPRESSOR ACTION AND TOXICITY 'ompounc No. Structure Pressor Action*/ Toxic ity Ref. Animal Relative Potency Animal Admin mgm, /kgm. 187 lsJ-CH2.CH2.NH2 cat 183 98 188 equals No. : 15 X-X' CH2. CH-CH3 dog dog 100 620 mouse rabbit i.p. i. v. LD50, 114 LD50, 35 9 109 189 NH2 190 XgX*i CHâ CH'CH3 CH3 NH2 dog less active than No. 188 rabbit i. v. LD50. 63 109 ^ .CH2.CH2.NH2 rabbit variable - often de- 33, pressor 101 191 ii y . (" i.3 â¢> . C*H . f H 7 dog 300 mouse i.p. LD50, 348 9 NH2 192 . CH2. CH2-NH2 cat depressor 101 OH 193 rV"VNH2 cat variable 101 oy 194 HO.-^^ cat depressor 101 c/kO 195 rr^ cat depressor 101 k^A^X . CH2CH2- NH2 See footnote, Table I. p. 75
98 Z. The Effect of Structural Modification of Sympathomimetic Amines on Bronchodilator Action In the preceding section, the vasopressor and depressor actions of sympathomimetic amines have been described. These effects are the net resultant of several factors such as vasoconstriction, alterations in the rate and amplitude of cardiac contraction and, in some instances, alterations in the respiratory movements of the thorax and diaphragm. Thus, a weak vasodilator drug which stimulates the heart or increases the amplitude of respiration may actually cause a rise in blood pressure due to increased filling of the arterial side of the vascular system. Inhibitory sympathomimetic potency can be determined more accurately when only a single organ is involved and where the predominant response is one of inhibition. The smooth muscles of the bronchioles are convenient for such an evaluation. Isolated lung preparations have been most often used for this purpose and the method of Sollmann and von Oettingen as modified by Tainu,r' n has become a standard screening test for the evaluation of sympathomimetic bronchodilator action. The bronchodilator action of various phenyl and hydroxyphenyl derivatives is shown in Table XIX. Most of the phenyl compounds either cause bronchoconstriction or are ineffective. TABLE XIX BRONCHODILATOR ACTION OF SYMPATHOMIMETIC AMINES PHENYL AND HYDROXYPHENYL DERIVATIVES .CH-CHX.NHY R Compound No. Structure 4 3 R X Y Bronchodilator Action Ref. Preparation Relative Potency*/ 24 H H OH H H cat, dog inactive 96 6 H H CH3 H H rabbit constricts 38 5 H H H CH3 H rabbit guinea pig constricts constricts 37.38 103 25 H H OH CH3 H guinea pig constricts 103 31 H H OH CH3 CH3 guinea pig 385 103 127 NH2 H OH CH3 CH3 guinea pig 178 103 120 OH CH3 OH CH3 H guinea pig constrictor 103 42 OH H H H H cat, dog constricts 95 48 OH H OH H H guinea pig inactive 66 49 OH H OH H CH3 guinea pig dog, cat weak 375 66 42 SO OH H OH H C2H5 guinea pig weak 66 51 OH H OH H CH(CH3)2 guinea pig weak 66 68 H OH OH H H guinea pig inactive 67
99 TABLE XIX (Cont.) Compound Structure 4 3 R X Y Bronchodilator Action Ref. No. Preparation Relative Potency^/ 69 H OH OH H CH3 guinea pig guinea pig (d,l) 63.7 (d. 1) >3000 103 67 dog weak 81a 70 H OH OH H CH(CH3)2 guinea pig 50-100 67 72 H OH OH CH3 CH3 guinea pig 21.7 103 1 -N-Ethylephedrine (No. 142) has a bronchodilator action in rabbit, cat and guinea pig lungs equal to that of ephedrine'Â°. Expressed as multiples of the effective dose of epinephrine Only ephedrine (No. 31) and the 4-aminophenyl analog (No. 127) induce measurable broncho- dilation and they are relatively weak drugs. The hydroxyphenyl derivatives in which the hydroxyl is in the 4-position are also quite weak or inactive. Compounds in which the hydroxyl is in the 3-position on the ring are distinctly more effective. Compound Nos. 69, 70 and 72 are moderately effective in dilating the bronchioles of the isolated guinea pig lung. A comparison of |3-(3,4-di- hydroxyphenyl)ethylamine (No. 76) and the N-methyl analog (No. 115) indicates that they are not significantly more effective than 1 -(3-hydroxyphenyl)-2-methylaminoethanol (No. 69). Greatest bronchodilator action is obtained when there are hydroxyl groups at both the 3- and 4-positions on the phenyl ring and when there is an alcoholic hydroxyl at C-2. The importance of the alcoholic group is illustrated by results obtained with compound Nos. 115 and 95. The former TABLE XX BRONCHODILATOR ACTION OF SYMPATHOMIMETIC AMINES - CATECHOL DERIVATIVES CH-CHX.NHY R Compound Structure R X Y Bronchodilator Action Ref. No. Preparation Relative Potency.^/ 76 H H H dog, cat guinea pig guinea pig 50 weak 350 10 10 60 196 H CH3 H dog, cat 50 10 115 H H CH3 guinea pig dog 50. 5 10-20 103 22 117 H H CH(CH3)2 guinea pig 15O 62 111 0: H CH3 guinea pig 167 62
100 TABLE XX (Cont. ) Compound No. Structure R X Y Bronchodilator Action Ref. Preparation Relative Potency^ 90 OH H H guinea pig (d,l) 7.4 (d,l) 280 103 64 (d,l) 10-14 (1) 17 (d) 1000 79 71 71 95 OH H CH3 guinea pig (1) 1.0 96 OH H C2H5 guinea pig 1.0 87 100 OH H CH(CH3)2 guinea pig 0. 12 62 97 OH H C3H7 guinea pig guinea pig 6-10 79 86 0.5 98 OH H C4Hg guinea pig 0.72 86 99 OH H C5H1 1 guinea pig 0.30 86 101 OH H CH(CH3)CH2.CH guinea pig 1.0 87 102 OH H C(CH3)3 guinea pig 0.2 79 104 OH H cyclopentyl guinea pig 0.05-0. 1 86 107 OH H cyclohexyl guinea pig 0.6-0.8 86 130 OH CH3 H guinea pig dog 14.7 100 approx. 103 22 133 OH CH3 CH(CH3)2 guinea pig very weak 67 131 OH C2H5 H guinea pig 71. 1 6.1 103 63 134 OH C2H5 CH(CH3)2 guinea pig 0.45 63 135 OH C2H5 cyclopentyl guinea pig 0.12 63 137 OH C2H5 cyclohexyl guinea pig 6 63 See footnote, Table XIX, p. 99 ('Epinine') has only one-tenth to one-fiftieth as much bronchodilator action as the latter (epin- ephrine). The primary amine, 1 -(3,4-dihydroxyphenyl)-2-aminoethanol (arterenol, No. 90) is a weak bronchodilator agent. N-Alkylation greatly increases potency. Epinephrine appears, to be at least seventeen times more active than the primary amine (arterenol). The N-isopropyl derivative (No. 100, 'Isuprel') is eight to ten times more effective than epinephrine. A further increase in potency is obtained when the N-alkyl group is cyclopentyl (No. 104). Lengthening of the side chain does not increase bronchodilator action. Compounds with four carbons in the side chain (Nos. 134-137) are somewhat less effective than the corresponding analogs in which there are only two carbons. Almost no bronchodilation was observed with l-(3, 4-dihydroxyphenyl)-2-
101 isopropylaminopropanol (No. 133). These data suggest that the order of importance of the various svibstituents is: (1) alcoholic hydroxyl at C-2, (2) an N-alkyl substituent, (3) an hydroxyl at the 3-position on the ring and (4) hydroxyls at the 3- and 4-positions. 3. The Effect of Structural Modification of Sympathomimetic Amines on Uterine Action The uterus may be either stimulated (contracted) or inhibited (relaxed) by sympathomim- etic amines. Results obtained with isolated non-gravid uteri are shown in Tables XXI and XXII. TABLE XXI THE EFFECT OF SYMPATHOMIMETIC AMINES ON UTERINE MOTILITY - PHENYL AND HYDROXYPHENYL DERIVATIVES CH- CHX-NHY R Compound No. Structure 4 3 R X Y Uterine Action3' Ref. Animal Action Relative Potency**/ 3 H H H H H rat \sl weak 66 guinea pig E weak 24,66 rabbit E. I or N 51,66 19 H H CH3 H CH3 rabbit E very weak 109 guinea pig E very weak 109 24 H H OH H H rabbit E 280 72 rabbit E 51 guinea pig E 24 30 H H OH H CH3 guinea pig E 24 35 H H OH H C4H9 guinea pig E 24 25 H H OH CH3 H rabbit E 51 31 H H OH CH3 CH3 guinea pig E 24, 51 rat I 5000 35 42 OH H H H H rabbit E, E or I 28 rabbit E 66 rat I 300,000- 2, 35, 1,000,000 66 cat E or I 28 guinea pig E 66 48 OH H OH H H rat I 66 rabbit E 66 guinea pig E 66 49 OH H OH H CH3 rat I 66 rabbit N 66 guinea pig N 66 cat I 70-100 58
102 TABLE XXI (Cont. ) Compound No. Structure 4 3 R X Y Uterine Action.3/ Ref. Animal Action Relative Potency.^ 50 OH H OH H C2H5 rat I 66 66 rabbit I guinea pig N 66 51 OH H OH H CH(CH3)2 rat rabbit I I 66 66 guinea pig N 66 57 OH H OH CH3 H rabbit E or I 51 68 H OH OH H CH3 rat rabbit I 10 59 19a E 71 H OH OH CH3 H rabbit guinea pig E 51 51 E 142 1 -N-ethylephedrine guinea pig rabbit E weak weak 16 E 16 Isolated non-gravid uteri were used Multiples of the effective dose of epinephrine E, contraction; I, relaxation; N, no effect The phenylalkylamines are excitatory substances of relatively low potency (except in the case of the rat in which uterine relaxation is obtained with all sympathomimetic amines). The presence of an alcoholic hydroxyl at C-2 is not alone sufficient for inhibitory action. This action is not apparent, to a significant degree, until three of the four important substitutions have been made. Compound Nos. 49, 50 and 51 containing an hydroxyl group at the 4-position on the ring, an alcoholic hydroxyl at C-2 on the side chain and an N-alkyl group are predominantly inhibitory in action. Relatively slight changes in structure cause a return of excitatory action. This is illustrated by the predominantly excitatory compounds, 1-(4-hydroxyphenyl)-2-aminoethanol (No. 48), in which the N-alkyl group is missing and by tyramine (No. 42) in which both the N-alkyl group and the hydroxyl at C-2 are missing. The catechol derivatives (Table XXII) may induce either contraction or relaxation, depend- ing upon the kind of substitutions made at C-2 and at N. Hydroxytyramine (No. 76) has been reported to have a weak inhibitory action on the rat and cat uterus.", 42. The N-methyl analog ('Epinine', No. 115) is excitatory to the rabbit uterus. The presence of an alcoholic group at C-2 increases excitatory action. Epinephrine (No. 95) is four times more potent than 'Epinine'. The primary amine (arterenol, No. 90) is only slightly less potent than epinephrine. Inhibitory action is dominant with N-alkylarterenols in which the alkyl substituent is larger than ethyl. Branching of this group is important inasmuch as both the N-ae_c.. -butyl (No. 101) and N-i. -butyl (No. 102) compounds are more active than the N-n. -butyl analog (No. 98). When the side chain is increased to four carbons, inhibitory action is weak in the absence of an N-alkyl group (No. 131). However, both the N-isopropyl and N-cyclopentyl analogs (Nos. 134 and 135) are potent inhibitory agents. The N-cyclohexyl (No. 137) analog is weak. In this respect, the cyclopentyl group most nearly resembles the isopropyl and 1. -butyl groups (see Sec. 1).
103 TABLE XXII THE EFFECT OF SYMPATHOMIMET1C AMINES ON UTERINE MOTILITY - CATECHOL DERIVATIVES HO . HO/ VCH.CHX.NHY \=/ Compound No. Structure R X Y Uterine Action* Ref. Animal Action Relative Potency 76 H H H cat I 90 42 rat I 2000-6000 35 115 H H CH3 rabbit E 4 64 rat I 20 62 rat I 120 35 117 H H CH(CH3)2 rabbit I 400 64 rat I 10 62 111 0: H CH3 rabbit E 400 64 rat I 2 62 rat I 25 35 114 O: H CH(CH3)2 rabbit N 64 90 OH H H rabbit (d,l) E 4-5 64. Ill rabbit (1) E 1 71 guinea pig (1) E. I 10-20 71,79 rat (d.l) 100 111 rat (1) I 30 71 . rat (1) I 10 62 cat (d,l) I 10 111 95 OH H CH3 rabbit (1) E 1.0 guinea pig (1) E.I 1. 0 rat (1) I 1.0 96 OH H C2H5 rabbit E 4 64 guinea pig E 40 64 guinea pig I 10 79 rat I 0. 5-1.0 35 100 OH H CH(CH3)2 rabbit I 1. 0 64 guinea pig I 1.0 64 rat I 0.5-1.0 35 98 OH H C4Hg rabbit I 40 64 guinea pig I 40 64 101 OH H CH(CH3) CH2.CH3 rabbit I 1. 0 64 guinea pig I 2.0 79 102 OH H C(CH3)3 rabbit I 4. 0 64 guinea pig I 40. 0 64 guinea pig I 2.0 79
104 TABLE XXII (Cont. ) Compound No. Structure R X Y Uterine Action3/ Ref . Animal Action Relative Potency 131 OH C2H5 H guinea pig I weak 63 134 OH C2H5 CH(CH3)2 guinea pig I 2.0 63 135 OH C2H5 cyclopentyl guinea pig I 2.0 63 137 OH C2H5 cyclohexyl guinea pig I weak 63 See footnote, Table XXI, p. 102 The non-gravid uteri of most species of animals are stimulated by phenylalkylamine derivatives. Both excitatory and inhibitory actions may be increased when there is an alcoholic hydroxyl present at C-2. Inhibitory action is enhanced by N-alkyl substitution, particularly by branched groups such as isopropyl or i. -butyl. The significance of this grouping has been recently reviewed" and will be discussed in this communication in the summary section. The above data suggest that inhibitory action on the uterus is favored by substitution, in the order (1) an alcoholic hydroxyl at C-2, (2) N-alkyl substitution, (3) an hydroxyl at the 4-position on the phenyl ring and (4) hydroxyls at the 3- and 4-positions. Excitatory action is favored by (1) hydroxy substitution of the ring at the 3- and 4-positions, (2) an alcoholic hydroxyl at C-2 and (3) by a N-methyl group. 4. The Effect of Structural Modification of Sympathomimetic Amines on Intestinal Action Results obtained with isolated intestinal segments are shown in Tables XXIII and XXIV. In the absence of an hydroxyl at C-2, the predominant action is excitatory (No. 3). Inhibitory and excitatory actions have been reported for 1-phenyl-2-aminoethanol (No. 24). The N-alkyl derivatives of No. 24 are inhibitory. The phenylpropylamines (Nos. 5,25 and 31) are variable TABLE XXIII THE EFFECT OF SYMPATHOMIMETIC AMINES ON INTESTINAL MOTILITY - PHENYL AND HYDROXYPHENYL DERIVATIVES CH. CHX. NHY R Compound No. Structure 4 3 R X Y Intestinal Action^/ Ref. Animal Part Action Relative Potency.^ 3 H H H H H guinea pig ileum EÂ£/ weak 66 rabbit sm. int. E, I weak 24 rabbit ileum E 51 rabbit colon E 51
105 TABLE XXIII (Cont. ) Com- lound No. Structure 4 3 R X Y Intestinal Action^/ Ref. Animal Part Action Relative Potency h/ 24 H H OH H H rabbit duodenum I i 1200 96 cat sm. int. I,E weak 96 rabbit s m . i nt . I 24 rabbit ileum E, 1 51 rabbit colon I 51 30 H H OH H CH3 rabbit I 24 34 H H OH H CH(CH3)2 guinea pig ileum I weak 66 35 H H OH H C4H9 rabbit sm. int. I 24 5 H H H CH3 H rabbit jejunum I weak 109 25 H H OH CH3 H rabbit rabbit ileum colon I I 51 51 31 H H OH CH3 CH3 rabbit rabbit sm. int. ileum E E,I 24 51 rabbit colon E, I 51 19 H H CH3 H CH3 rabbit jejunum I weak 109 42 OH H H H H guinea pig rabbit ileum sm. int. N E 66 95 cat sm. int. E.I 95 rabbit sm. int. I.E 80 48 OH H OH H H rabbit jejunum I 500 78 49 OH H OH H CH3 rabbit rabbit jejunum sm. int. I 500 100 78 58 I rabbit ileum I 51 rabbit colon I 51 (1) rabbit sm. int. I 1000- 10,000 31 50 OH H OH H C2H5 rabbit guinea pig jejunum ileum I I 500 weak 78 66 51 OH H OH H CH(CH3)2 rabbit guinea pig jejunum ileum I 500 weak 78 66 I 55 OH H OH H C(CH3)3 rabbit guinea pig jejunum ileum I I <500 weak 78 66 53 OH H OH H C4H9 rabbit jejunum ileum I N 500 78 66 guinea pig 57 OH H OH CH3 H rabbit rabbit ileum colon I 51 51 I 69 H OH OH H CH3 rabbit rabbit sm. int. sm. int. I I 12 59 31 10
106 TABLE XXIII (Cont. ) Compound No. Structure 4 3 R X Y Intestinal Action^/ Ref Animal Part Action Relative Potency^ 71 H OH OH CH3 H rabbit rabbit ileum colon I I 51 51 Isolated intestinal segment used L. " a Multiples of the effective dose of epinephrine Â£/ E, contraction; I, relaxation; N, no effect in action and may cause either excitation or inhibition. Tyramine, like f)-phenylethylamine, is excitatory. The addition of an hydroxyl at C-2 givea rise to compounds that are inhibitory. Thus 1-(4-hydroxyphenyl)-2-aminoethanol is predominantly inhibitory whereas tyramine may cause excitation. Comparison of 1 -(3-hydroxyphenyl)-2-methylaminoethanol (No. 69) with 1-(4-hydroxy- phenyl)-2-methylaminoethanol (No. 49) suggests that the hydroxyl at the 3-position on the ring is more important than that at the 4-position. The former compound is ten to fifty times more potent than the latter. Substitution of hydroxyls at the 3- and 4-position on the ring in the absence of an hydroxyl at C-2 (No. 76) gives an inhibitory compound but the inhibitory action does not exceed that of 1 -(3-hydroxyphenyl)-2-methylaminoethanol. The subsequent addition of an hydroxyl at C-2 (No. 90. arterenol) causes a marked increase in inhibitory potency. TABLE XXIV THE EFFECT OF SYMPATHOMIMETIC AMINES ON INTESTINAL MOTILITY CATECHOL DERIVATIVES Hy~\ lOf VCH. CHX-NHY Compound No. Structure R X Y Intestinal Action** Ref. Animal Part Action Relative Potency 76 H H H rabbit sm. int. I 20-40 42 cat sm. int. I 17 42 115 H H CH3 guinea pig guinea pig rat ileum ileum colon I I.E* I 17 5, 1-2.5 100-200 62 64 35 117 H H CH(CH3)2 guinea pig ileum I 200 35 111 O: H CH3 rabbit guinea pig sm. int. ileum colon I 25-50 20 20 51 64 35 rat I I 114 0: H CH(CH3)2 guinea pig ileum N 64
107 TABLE XXIV (Cont. ) Compound No. Structure R X Y Intestinal Action^/ Ref. Animal Part Action Relative Potency 90 OH H H (d, 1) rabbit sm. int. I 2 51 (4,1) rabbit jejunum I 2-4 79 (d, 1) rabbit ileum I 2 111 (1) rabbit ileum I 1 71 (il) rabbit ileum I 60 71 (d, 1) cat ileum I 1 111 (d, 1) rat ileum I 3 11 1 (d, 1) guinea pig ileum I 5 64 (d, 1) guinea pig ileum I 2 79 (1) guinea pig ileum I 1.37 71 (d) guinea pig ileum 1 35-40 71 (1) guinea pig ileum I 0. 5 62 (d. 1) rat colon I 0. 2-1. 0 35 96 OH H C2H5 rabbit jejunum I 4 79 guinea pig ileum I 2 64 100 OH H CH(CH3)2 rabbit ileum I 2 79 guinea pig ileum I 1-2 62, 79 rat colon I 1 35 101 OH H CH(CH3)CH2CH , rabbit jejunum I >20 79 guinea pig ileum I 1-2 64 102 OH H C(CH3)3 rabbit jejunum I >20 79 guinea pig ileum I 10-20 64, 79 98 OH H C4H9 guinea pig ileum I 20 64 134 OH C2H5 CH(CH3)2 guinea pig ileum I 110 63 135 OH C2H5 cyclopentyl guinea pig ileum I 100 63 137 OH C2H5 cyclohexyl guinea pig ileum I 320 63 See footnote, Table XXIII, p. 106 The major portion of this activity is attributable to the 1-isomer. The d-isomer has only one- thirty-fifth to one-fortieth the activity of the l-isomer?l. Comparison of results obtained with epinephrinc, which is the 1-isomer of the N-methyl analog, indicates that these 1-isomers are of comparable potency. The substitution of larger groups for the N-methyl group does not increase intestinal inhibitory action. Thus the N-isopropyl derivative (No. 100, 'Isuprel i is approximately equal to cpincphrine and arterenol; the N-s_Â£Â£. -butyl and N-t. -butyl derivatives are less potent. An increase in the size of the side chain to four carbons is not favorable for inhibitory action. Thus the hutanol derivative, No. 134, is distinctly less potent than the corresponding ethanol derivative, No. 100.
108 Youman.*.. Aun-iann and Haneyl'2 have made a qualitative comparison of intestinal inhibitory action of several sympathomimetic amines in dogs with Thiry-Vella fistulas. The drugs were administered intravenously and the response to epinephrine was used as a basis for comparison. The drugs studied with results, expressed in terms of the effective dose of epinephrine, are shown below: epinephrine (d,l) arterenol (No. 90) 'Cobefrine' (No. 130) 'Epinine' (No. 76) 'Kephrine' (No. Ill) 'Neo-Synephrine'(1, No. 'Sympatol' (No. 49) 69) 1.0 1.5-4.0 2. 5-10.0 10-25 25-100 25-100 660-2500 These results are in general agreement with those obtained with the isolated intestinal segment. Addition of an hydroxyl at C-2 increases inhibitory action ten to twenty-five times ('Epinine' vs. epinephrine). A comparison of the activity of (1) 'Neo-Synephrine' with that of (d,l) 'Sympatol1 reveals the importance of the hydroxyl at the 3-position on the ring. Although the comparison is made with the 1-isomer of the former and the d, 1 form of the latter, the results obtained suggest different orders of activity, the 3-hydroxyphenyl analog being about ten times more potent than the latter. The data in Tables XXIII and XXIV suggest that intestinal excitatory action of phenylalkyl- amine derivatives is weak and is suppressed or obscured by any one of the four basic substitutions. In the presence of an hydroxyl at C-2, inhibitory potency is increased by substitution of an hydroxyl (1) at the 3-position on the phenyl ring and (2) at the 3- and 4-positions on the ring. An N-alkyl group does not appear important for this action. 5. The Effect of Structural Modification of Sympathomimetic Amines on Central Nervous System Stimulation A quantitative comparison of the stimulating action of sympathomimetic amines on the central nervous system has been made in a few instances. These data are shown in Table XXV. TABLE XXV STIMULATING ACTION OF SYMPATHOMIMETIC AMINES ON THE CENTRAL NERVOUS SYSTEM ' \ CH-X NHY R Com- Structure 4 3 R X Y Central Nervous System Stimulation Ref. Minud No. Animal Dose Used mgm. ,/kgm. Admin. Effect 3 H H H CH2 H rat mouse 80 30 s. c. i.p. â¢f + 85 48 30 H H H CH2 CH3 rat mouse 160 >50 Â». c. i.p. + + 85 48 4 H H H CH2-CH2 H rat >10 s. c. 0 85
109 TABLE XXV (Cont. ) Comp pounc No. Structure 4 3 R X Y Central Nervous System Stimulation Ref. Animal Dose Used mgm. /kgm. Admin. Effect 5 H H H CH(CH3) H rat rat mouse rat (d, 1) 2.5 (d, 1) 50 (d. 1) 0. 55 (d) 2. 5 (1) 10.0 s. c. oral i.p. s . c. s. c. â¢f + 85 .f + 48 109 85 85 18 H H H CH(CH3) CH3 rat rat rat (d,l) 0.25 (d) 0.125 (I) 2. 0 (d, 1) 0.9 s. c. s. c. â¢f .f 81 81 81 48 s. C. i.p. 19 H H CH3 CH2 CH3 rat 50 oral 0 109 9 H H H CH(C2H5) H mouse 8 i. p. + 48 13 H H H CH(C3H7) H mouse 14 i.p. + 48 197 H H H CH(CH.,) C2H5 rat 4 a. c. * 81 198 H H H CH(CH3) C4H9 rat >128 a. c. 0 81 199 H H H CH(CH3) C5H,, rat >128 a. c. toxic 81 25 H H OH CH(CH3) H rat 40 a. c. + 85 26 H H OH CH(C2H5) H rat >320 s. c. 0 85 27 H H OH CH(C3H7) H rat 320 s. C. * 85 28 H H OH CH(C4H9) H rat >80 s. C. 0 85 31 H H OH CH(CH3) CH3 rat rat (d, 1) 16 (D 5 (d) 40 (d.l) 19 s. c. 85 85 85 48 a. c. a. c. i.p. ; 42 OH H H CH2 H rat >320 s. c. 0 85 43 OH H H CH2 CH3 rat 160 s. c. * 85 44 OH H H CH(CH3) H rat 80 s . c. * 85 49 OH H OH CH2 CH3 rat >320 s. c. 0 85 58 OH H OH CH(CH3) CH3 rat >32 s. c. 0 85 76 OH OH H CH2 H rat 80 s. c. * 85 90 OH OH OH CH2 H rat rat >2 a. c. 0 85 71 (1) 0.25- 2.0 s. C. 95 OH OH OH CH2 CH3 rat 0.25 (d) >40 s. C. 85 85 s. C. 0
110 TABLE XXV (Cont. ) Com- pound No. Structure 4 3 R X Y Central Nervous System Stimulation Ref. Animal Dose Used Admin. Effect mgm. /kgm. 130 OH OH OH CH(CH3) H rat >5 B.c. 0 85 132 OH OH OH CH(CH3) CH3 rat >40 s. c. 0 85 131 OH OH OH CH(C2H5) H rat >160 s. c. 0 85 The most effective stimulating drugs are P-phenylisopropylamine (No. 5) and its N-methyl analog (No. 18). The d-isomers appear to be ten to twenty times more stimulating than the l-isomersÂ°'' . p-Phenylethylamine (No. 3) is almost inactive. An increase in the number of carbons in the side chain to four (1-phenyl-2-aminobutane, No. 9) or five (1 -phenyl-2-aminopentane, No. 13) decreases central excitatory action. Similarly, the substitution of groups larger than methyl at N causes a decrease in activity in the order methyl, ethyl, butyl, amylÂ°'. Substitution of an hydroxyl at C-2 greatly reduces excitatory action. 'Propadrine' (No. 25) and ephedrine (No. 31) are distinctly less potent than amphetamine (No. 5) and N-methylamphetamine (No. 18). Hydroxyl substitution on the ring is likewise unfavorable for stimulation of the central nervous system. The threshold stimulating dose of p-(4-hydroxyphenyl)isopropylamine (No. 44, 'Paredrine') is one- thirty-seconds that of amphetamineÂ®5. The hydroxyphenyl analog of methylamphetamine (No. 45, 'Paredrinol') is inactive. The corresponding catechol analogs (Nos. 133 and 135) also have been reported to be inactive. Jacobsen et al. " have reported results in man similar to the above data. Gunn and Gurd*' observed excitation in mice after intraperitoneal injection of various cyclohexylalkylamines. These results are not in agreement with those of Lands, et al."5, who compared N-methylcyclohexylisopropylamine (No. 159) with the corresponding phenyl analog and found that hydrogenation of the ring greatly reduced excitatory action. Swanson and Chen^2 found amphetamine forty times more potent than N-methylcyclopentylisopropylamine (No. 166). Aliphatic amines have little or no stimulating action on the central nervous system85. These data establish the importance of phenylisopropylamine (No. 5) for stimulation of the central nervous system. Modification of this basic structure diminishes or abolishes excitatory action. SUMMARY The most important modifications of the sympathomimetic actions of P-phenylethylamine are obtained by (1) substitution of the phenyl ring by an hydroxyl at the 3-position, (21 disubstitu- tion of the ring at the 3- and 4-positions, (3) substitution of C-2 of the side chain by an hydroxyl and (4) alkyl substitution of the aminr. ^ The relative importance of each of these substitutions in modifying the activity of p-phenylethylamine is difficult to determine by an examination of the published experimental data. Variations in test procedures and insufficient attention to quantitative methods of testing have given rise to important differences between the results obtained by different investigators. However, some generalizations are suggested by the data tabulated in this communication.
1ll The substitutions listed above differ in importance when different test organs are used. Excitation of the cardiovascular system is favored by an hydroxyl at the 3-position on the ring. The subsequent addition of the alcoholic hydroxyl causes a distinct increase in potency. However. the alcoholic hydroxyl does not appear to be the key structure for this action inasmuch as its presence causes a distinct reduction in pressor potency when the phenolic hydroxyl is in the 4-position on the ring. Methyl substitution of the nitrogen atom does not greatly influence pressor potency, except in the case of hydroxytyramine ('Epinine'). The pressor potencies of l-(3- hydroxyphenyl)-2-aminoethanol and 1 -(3, 4-dihydroxyphenyl)-2-aminoethanol are essentially the same as that of their N-alkyl analogs. When depressor action is considered, quite another picture is obtained. The substitution of the second carbon of the side chain of p-phenylethylamine by an hydroxyl causes a distinct reduction in pressor potency and this is further reduced by the addition of an hydroxyl to the ring at the 4-position and by an N-methyl group. If an N-ethyl or N-isopropyl be substituted in place of the N-methyl group, the dominant action of the compound is depressor. N-Isopropylarterenol ('Isuprel', 'Aleudrine') is a very potent vasodepressor agent. The removal of the alcoholic hydroxyl abolishes depressor action, a weak pressor response resulting in most instancesÂ°4. Ring hydroxyls are not necessary for depressor action inasmuch as 1 -phenyl-2-isopropylamino- ethanol is an effective depressor agent. The corresponding ethane analog is almost inactive^, indicating further the importance of the alcoholic hydroxyl for depressor action. Bronchodilator action is not usually obtained unless there is both an alcoholic hydroxyl at C-2 and a phenolic hydroxyl at the 4-position. Both 1 -(4-hydroxyphenyl)-2-methylaminoethanol and the 3-hydroxy analog are weak bronchodilator agents. Arterenol, with both hydroxyls on the ring, is somewhat more potent. The N-methyl analog (epinephrine) is fifty times, the N-isopropyl analog one hundred times more potent than the primary amine. The alcoholic hydroxyl is most important for this action. Thus, little or no bronchodilation is obtained with N-isopropyl-p- (3,4-dihydroxyphenyl)ethylamine. The structural requirements for bronchodilation and vaso- depression are apparently quite similar. Failure to obtain bronchodilation with weak vasode- pressor agents may result from the strong bronchoconstriction employed in the usual test methods. By contrast to the above results, inhibition of the intestine appears to be favored by structural modifications favorable for vasopressor action. The inhibitory action of 1-(4-hydroxy- phcnyl)-2-aminoethanol is about one-five hundredths that of epinephrine; the 3-hydroxy analog is about one-tenth to one-twelfth that of epinephrine. Addition of the second hydroxyl to the ring increases intestinal inhibitory potency as it does pressor action. The substitution of an N-methyl, N-ethyl or N-isopropyl group does not increase this action, these derivatives being no more effective than the primary amine. Removal of the alcoholic hydroxyl reduces potency but the resultant compound retains strong inhibitory action. The ethane analogs of arterenol and epineph- rine have one-fifth to one-fortieth the inhibitory potency of epinephrine. Uteri of various species differ greatly in their response to drugs. Pharmacologic evaluation is further complicated by differences in response resulting from variations in the physiological state of this organ. With the rat uterus, which is relaxed by all sympathomimetic amines, potency is greatly increased by the addition of the alcoholic hydroxyl. Gaddum et al. ^ reported 1-arterenol to be about twenty times more inhibitory than hydroxytyramine. The presence of an N-alkyl substituent causes some further increase in potency35, 63, 71. This is in general agreement with results obtained for vasodepression and bronchodilation. The responses of rabbit and guinea pig uteri are variable and these organs may be either contracted or relaxed by sympathomimetic amines. Although our data are incomplete, the results tabulated here suggest that the response obtained represents the net resultant of these two opposing actions. Weak sympathomimetic amines such as p-phenylethylamine or tyramine usually cause contraction. Relaxation is obtained when there is an alcoholic hydroxyl and/or an N-alkyl group larger than methyl. The N-isopropyl analog of hydroxytyramine is a weak uterine inhibitor. Addition of the alcoholic hydroxyl increases greatly this inhibitory action. The primary amine, arterenol, may either contract or relax the guinea pig uterus?l, 79 and the rabbit uterus is contracted. The presence of an N-alkyl group larger than methyl suppresses excitation, the balance now being favorable for relaxation. Inasmuch as both the N-alkyl group and the alcoholic hydroxyl are important for inhibition of the uterus, the inhibitory pattern of this organ most nearly resembles that of the vascular system and bronchioles. The effect of structural modifications of p-phenylethylamine divides these sympathetically innervated organs into two functional groups (l) vasodepressor action (relaxation of the arterioles and capillaries), brcmchodilation and uterine relaxation; (2) vasopressor action (contraction of the
I12 arterioles and capillaries), uterine contraction and intestinal relaxation. The alcoholic hydroxyl at C-2 on the side chain appears to be the key structure for the first and an hydroxyl at the 3- position on the phenyl ring for the second. The addition of each of the other substituents to the key compound will then increase potency, as indicated above. The relative effectiveness of sympathomimetic drugs on various other organs innervated by the sympathetic nervous system has been determined in some instances. These data are reviewed here in terms of the above generalization. Sympathomimetic action on the heart must be considered for effects on both rate and amplitude inasmuch as each of these actions may be influenced by drugs to a different degree. Effects on heart rate suggest that there is no distinct differentiation of effects such as is found with the peripheral vascular system. Structural modifications which favor either vasoconstriction or vasodilatation are favorable for cardiac acceleration. Thus, the highly potent vasodepressor drug, 1 -(3, 4-dihydroxyphenyl)-2-isopropyl- aminoethanol ('Isuprel') and the N-Â£. -butyl analog are about four to ten times more effective than epinephrine in increasing the rate^*, 79. Similarly, 1-(4-hydroxyphenyl)-2-isopropylaminoethanol is four times more effective than the corresponding N-methyl analog, 'Sympatol'?S An alcoholic hydroxyl at C-2 of the side chain is important. This is easily demonstrated with 1 -(3, 4-dihydroxy- phenyl)-2-isopropylaminoethanol and the corresponding ethane analog. The former compound is three hundred to five hundred times more potent than the latter. Excitatory action is retained in 1-phenyl-2-isopropylaminoethanol, indicating that the ring hydroxyls only increase potency. Â°* An hydroxy at the 3-position on the ring is more favorable for cardiac acceleration than at the 4- position. Comparison has shown 1-(3-hydroxyphenyl)-2-methylaminoethanol ('Neo-Synephrine') to be twenty to fifty times more stimulating than the 4-hydroxyphenyl analog ('Sympatol') in experiments on the denervated hearts of dogs. 112 Hydroxyls at both the 3- and 4-positions on the ring are more favorable than either alone. Racemic epinephrine is approximately ten to twenty- fives times more effective than 'Neo-Synephrine' and two hundred to twelve hundred times more effective than 'Sympatol'. From the above data it readily can be seen that each of the four substi- tutions to the p-phenylethylamine nucleus contribute importantly to cardiac accelerating action. There are little quantiative data available with regard to the effects of these drugs on the force of cardiac contraction. Garb^ has reported arterenol somewhat more effective than either epinephrine or 'Isuprel'. Similarly, Tainter has reported an increased force of contraction with arterenol which was greater than that obtained with epinephrine and more prolonged2Â°. Marsh et al. '" and Ahlquist* reported equal effects for d, 1-epinephrine and arterenol with the perfused cat and rabbit hearts but greater effect was obtained with 'Isuprel'. Removal of the hydroxyl at the 3-position on the ring reduces activity to about one-hundredth that of the corresponding catechol analog' . Crismon and Tainter26 found that the simpler amines, 'Propadrine', ephedrine and 'Benzedrine', exerted an influence on rate but were without important effect on amplitude. These data are in general agreement with those for effect on rate except for the effect of the N-methyl group, the primary amines being equal to or slightly more effective than the N-methyl analog in increasing the force of contraction. The cat nictitating membrane has been used as an indicator of excitatory action. Bacq, *' found epinephrine more effective than arterenol whereas Gaddum et al. 35 reported the two drugs equally potent. Removal of the hydroxyl from the 4-position only on the ring reduces activity to about one-quarter; from the 3-position only to about one-thirtieth to one-one hundred- twentieths that of epinephrine. The alcoholic hydroxyl is important for this action. Both 'Epinine' and 'Kephrine' are distinctly weaker than epinephrine. Hydroxytyramine has one-hundredth the stimulating action of epinephrine". Ahlquist found 'Isuprel' ineffective and Gaddum et al. ^ have reported relaxation of the nictitating membrane after injection of this drug. These data suggest that stimulation of the cat nictitating membrane is favored by the same structural changes which favor vasopressor action, uterine contraction and intestinal relaxation. Ahlquist* has postulated two receptors for sympathomimetic drug action; an alpha adrenotropic receptor for vasoconstriction in the viscera and skin, for contraction of the uterus and nictitating membrane and for relaxation of the intestine, ureter and dilator pupillae, a beta receptor for vasodilation in skeletal muscle, coronary vessels and viscera, for inhibition of the uterus and bronchioles and for cardiac stimulation. The data presented here are in general agreement with such a functional classification of organs innervated by the sympathetic nervous system. The key configuration for stimulation of the a-receptor probably is p-(3-hydroxyphenyl)- ethylamine with subsequent substitution of the alcoholic hydroxyl on the side chain and the second hydroxyl to the ring each increasing potency. N-Alkyl substitution is less important and may actually diminish potency with groups larger than methyl. The key configuration for stimulation
113 of the p-receptor is probably 1-phenyl-2-aminoethanol, the alcoholic hydroxyl at C-2 of the side chain playing an important role. Substitution of an hydroxyl at the 4-position on the ring and N-alkyl substitution each increase inhibitory potency. With both key structural requirements present in the molecule, mixed effects are frequently observed, as for example the responses which follow an intravenous injection of epinephrine. The cardiac receptor for sympathomimetic drug action either is different from those described above or is undifferentiated and may be considered as an a p structure, responding to both excitatory and inhibitory drugs by increased cardiac action. Lengthening of the side chain decreases both excitatory and inhibitory actions. The propanol derivative, 'Cobefrine', is somewhat less pressor than the ethanol derivative, arterenol. An increase in the number of carbon atoms in the side chain to four practically abolishes pressor action. Inhibitory action on the bronchioles, uterus and intestine are also diminished. These results suggest that stimulation of both the a and p systems is diminished. Further evidence of this is furnished by the low stimulating action of this compound on the hearvO , an organ in which both functional systems may cause increased action. Modification of the key compounds, as indicated above, causes similar changes inaction. Thus, I-(3-hydroxyphenyl)-2-aminopropanol is approximately ten times more pressor than 1 -(4-hydroxyphenyl)-2-aminopropanol"* ". The alcoholic hydroxyl at C-2 does not increase vasopressor action, in the absence of an hydroxyl at the 3-position on the ring. This is readily seen by comparing the pressor action of p-(4-hydroxyphenyl)isopropylamine with that of 1 -(4-hydroxyphenyl)-2-aminopropanol. The former is 1.5-2.0 times more effective than the latter"- 24, 100 The presence of an N-alkyl group increases stimulation of the p-receptor. The action of 1 -(3, 4-dihydroxyphenyl)-2-methylaminopropanol is predominantly depressor4,84; that of 1 -(3, 4-dihydroxyphenyl)-2-isopropylamino-l -butanol strongly depressor but less so than 'Isuprel'63. Again, using the heart as an indicator of the sum of sympathomimetic action, we find the stimulating action of 1 -(3, 4-dihydrpxyphenyl)-2-isopropylamino-l -butanol much weaker than 'Isuprel'. The data shown in Table XV suggest that hydrogenation of the phenyl ring abolishes stimulating action on the p-receptor but only diminishes stimulation of the a-receptor. The pressor action of p-cyclohexylethylamine and 1 -cyclohexyl-2-methylaminoethanol is about one- half that of the corresponding phenyl analogs41, 60, 74. The cyclohexyl analog of the effective vasodepressor compound, 1-(4-hydroxyphenyl)-2-isopropylaminoethanol, is inactive^O. The effect of cyclopentyl or o-thienyl substitution in place of the phenyl ring likewise reduces pressor potency. Available data do not permit other comparisons. Aliphatic amines appear to stimulate the a-mechanism but have little or no effect on the P-mechanism. Thus, they generally raise blood pressure but cause bronchoconstriction and contraction of the intestine and uterus8- 30, 76, 101 Two of these, 'Octin' and 'Tuamine' have clinical importance as vasoconstrictors. Excitatory action on the central nervous system observed with some sympathomimetic amines does not fit into the pattern of action previously described. The most effective stimu- lating drugs are phenylisopropylamine and its N-methyl analog. An increase in the length of the side chain or of the N*alkyl group reduces central excitatory effect. Substitution of an hydroxyl on the side chain or on the ring greatly diminishes or abolishes excitation"' . " . Ephedrine (alcoholic hydroxyl at C-2) is about one-sixteenth as active as amphetamine; 'Paredrine' (phenolic hydroxyl at the 4-position) has almost no stimulating action"->. Epinephrine has been reported to cause some stimulationÂ®5. Gaddum and Kwiatkowski34 anIj Lawrence, Morton and Tainter"8 have reported potentiation of the pressor action of epinephrine by ephedrine and suggested that this might be due to the inhibition of amine-oxidase thus preventing the destruction of epinephrine. Similar action has been reported by Jang56 for 'Benzedrine" and 'Propadrine'. One might assume that the stimulation observed with these drugs is secondary and results from the protection of epinephrine, produced naturally at synaptic junctions, from enzymatic destruction. This seems improbable in the light of the results obtained by Lewis"' who observed marked epinephrine potentiation with various aliphatic amines, although aliphatic amines have been reported to be devoid of central stimulating action?"' 85 Another barrier to the acceptance of this concept is suggested by the work of Marrazzi and Bulbring and BurnZ' who have shown that physiological quantities of epinephrine inhibit synaptic transmission in sympathetic ganglia. The observed elevation of mood and increased alertness that follow amphetamine or N-methylamphetamine could hardly result from increased synaptic resistance, if these central synapses are similar to
I 14 those in sympathetic ganglia. The stimulating action of these amines on the central nervous system appears to involve receptor systems other than the a and p types found in sympathetically innervated organs. This review of sympathomimetic amines, has listed representative data of the type usually supplied by the pharmacologist to the medicinal chemist as a guide to further synthesis. It is the hope of the writer that such a collection will be useful to those engaged in the synthesis and evaluation of sympathomimetic drugs. The limitations of the data are obvious. It is readily apparent that these correlations are based upon a two-dimensional picture of a three-dimensional structure. There is also relatively little known about differences in physical and chemical properties of these molecules which may contribute importantly to the physiologic actions observed. Future research must provide us with information with regard to the nature of the reactions that take place within the effector organs and elucidate the importance of structural variation on these reactions. The progress of sympathomimetic drug research during the first half of this century is of such magnitude that we may look forward to the second half century with great expectations. It may not be too much to hope that, as a result of an increasing life expectancy, many of us who have participated in the work of the first half may witness also the full achievements of the second half century. *********** 'Suprarenin', 'Isuprel', Cobefrine', 'Neo-Synephrine', 'Sympatol', and 'Kephrine' are trademarks of Winthrop-Stearns Inc. 'Vonedrine' is the trademark of the Wm. S. Merrell Company. 'Aleudrine' is the trademark of National Drug Company. 'Epinine' is the trademark of Burroughs, Wellcome and Company. 'Propadrine' is the trademark of Sharp and Dohme, Inc. 'Paredrine', 'Paredrinol' and 'Benzedrine' are trademarks of Smith, Kline and French Laboratories. â 'Octin' is the trademark of Bilhuber-Knoll Corp. 'Tuamine' is the trademark of Eli Lilly and Company.
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120 DISCUSSION DR. T. C. BARNES (Hahnemann Medical College and Hospital of Philadelphia): I should like to congratulate Dr. Lands on this fine paper and I should like to know if he would consider the possibility that the structural modifications of drug molecules have electrical effects which may explain their action. We have found that a series of sympathomimetic drugs have distinctive phase-boundary potentials. A triglyceride oil is capable of picking out sympathomimetic drugs from a solution and leaving all the parasympathetic drugs in the aqueous medium. We feel that structural modifications such as those described by Dr. Lands are simply factors which influence the oil solubility of the compounds and the extent of their ionization within the oil phase. Thus the pharmacodynamic action on the tissue may be produced by the electrical potential generated by the drug. / SEC Oil-cell apparatus for measuring phase-boundary potentials of drugs.
121 (Slide) Our methods are rather unusual so I am showing this slide of the glass tube containing the oil layer forming a phase-boundary with saline. With triacetin in the apparatus electrical potential is generated with sympathomimetic drugs but not by acetylcholine. (Slide) This shows the apparatus for producing phase-boundary potential directly on nerve. We extract some of the lipoid from the frog sciatic with ether and treat the nerve with the adrenergic oil-triacetin. The nerve gives a greater potential with amphetamine than it did before the triacetin was added. Nerve from an animal not having an adrenal Like the lobster is not sensitized in this way. We believe that the sympathetic and parasympathetic nerves contain different lipoid. (Slide) This apparatus shows a glass model of a cellular receptor upon which a drug is supposed to act. The center capillary tube is filled with an adrenergic oil on which amphetamine for example produces the same negative potential as it does on a wide surface of oil 5 cms. in diameter. In other words, membrane potential is independent of area. There is no need to postulate the presence of receptor spots on living cells. (Slide) This shows the Speedomax chart of the negative phase-boundary potential produced by tyramme on triacetin. Tyramine can be used to detect adrenergic oils. Catechol is electrically inactive. (Slide) This shows a series of parasympathetic and sympathetic drugs which were tested on adrenergic oils. Acetylcholine. curare, methacholine and atropine are inactive on triglyceride oil on which the sympathomimetic drugs generate potential (including the aliphatic members, octin, oenethyl and aranthol). Nicotine is also active on adrenergic oils suggesting its pressor action is related to that of epinephrine. ACTIVITY OF CHEMICALS ON ANDRENERGIC O\LS (all concentrations 0. 05%) Acetylcholine 0 Choline 0 Mecholyl 0 Pilocarpine 0 Eserine 0 Prostigmine 0 Atropine 0 Curare 0 Etamon 0 Aranthol 19 millivolts Octin 32 millivolts Oenethyl 15 millivolts Priscol 45 millivolts Yohimbine 77 millivolts Dibenamine 6 millivolts In view of the above evidence I should like to ask Dr. Lands if he would agree that the phase-boundary potential of an adrenergic drug is a factor in its pharmacodynamic action on the living cell. We suggest that epinephrine, for example, stimulates the heart exactly like an electric current.
122 PR: MARRAZZI (Department of the Army, Army Chemical Center. Maryland): I think it will be apparent that the data have carried us or, rather Dr. Lands, far in the correlation of structure to function. I believe another point of view might carry us further, even more signifi- cantly further, and deserves some emphasis. Lest your first impression be that the addition of an unnecessary complication is involved, I would like to call your attention, very briefly, to some preliminary considerations. Recapitulating some of Dr. Lands' remarks, the characteristic activity of what we might call the sympathomimetic nucleus, namely the p-phenylethylamine group, is that it will, in fact, exhibit all of the actions of the sympathomimetic amines. All of the actions in the case of sympathomimetic amines can be readily divided into two types, and summarized as excitatory and inhibitory actions; that is, the stimulating action on the heart, for example, is an excitatory action; the bronchodilator action is an inhibitory action. The sympathomimetic nucleus mentioned is the basic member of the series (p-phenyliso- propylamine is the basic member of an analogous series) in which the commonest substituents, i.e. a meta phenolic hydroxyl, a para phenolic hydroxyl, an alcoholic hydroxyl on the beta carbon and a methyl group on the nitrogen, all four individually or collectively (adrenaline) always produce enhancement of both types of characteristic activity. Whether you agree with me in detail or not, the point I would like to make is that these modifying groups here and, possibly, with other compounds, are producing a multiplicity of actions which ordinarily can be summarized into a few groups, usually into excitation and inhibition; and that, for fundamental understanding, it is sufficient to focus on only one action or on one type of action because, ordinarily (in fact, I know of no exceptions), all of the actions are simultaneously being affected. So I would plead for further emphasis on what you occasionally saw in Dr. Lands' slides; namely, a correlation to both types of action simultaneously or to the ratio of excitatory to inhibitory actions or the other way around, as may be desired. Since a change in chemical constitution produces a simultaneous change in all of the activities elicited by a compound, one can only hope to correlate the chemical change to the complete picture of activity. Obviously, there will be difficulties. One will have to choose an excitatory action which is characteristic of the whole group, and an inhibitory action characteristic of the whole group. One of the final remarks Dr. Lands made may have been left in your memory as a possible conspicuous exception to the ready classification of actions into related excitatory and inhibitory groups. He pointed out that the inhibitory action of adrenaline on the brain which we'l^a) have described, would seem to be quite different from and unrelated to any other central action but this is because one has been familiar hitherto with only the central so called excitatory actions of sympatho- mimetic amines. We have, however, described a cerebral inhibitory action for adrenaline and several other sympathomimetic amines which is characteristically similar to the one we have previously described in sympathetic gangliaZ(' 3Â°) and shown to be analogous.M*73) to inhibition at adrenergic neuroeffector junctions. Thus in keeping with the concept we are proposing, even these central actions of the sympathomimetic amines are apparently divisible into excitatory and inhibitory and for adequate, more meaningful and accurate analysis the correlation of chemical structure should be made to something expressing both actions, i.e. to the ratio of the two. References 1. Marrazzi, A. S. , The central inhibitory action of adrenaline and related compounds. Fed. Proc., 2, 33 (1943). Marrazzi, A. S. and Hart, E.R., Cerebral synaptic responses to drugs as counterparts of possible humoral mechanisms. J. Pharmacol. , 98, 22 (1950). 2. Marrazzi, A. S. , Electrical studies on the pharmacology of autonomic synapses. II. The action of a sympathomimetic drug (epinephrine) on sympathetic ganglia. J. Pharmacol. , 65, 395 (1939). Marrazzi, A. S. and Marrazzi, R. N. , Further localization and analysis of adrenergic synaptic inhibition. J. Neurophysiol. , 10. 167 (1947).
123 3. Marrazzi, A. S. , Reduction of sympathetic synaptic transmission as an index of inhibition at adrenergic junctions in general, Science, 104, 6 (1946). DR. LANDS: With regard to Dr. Barnes' comments, I think it probable that sympatho- mimetic amines act at some easily accessible surface inasmuch as the effect is rapidly elicited and readily reversed. However, I would prefer to ask Dr. Barnes a question rather than attempt to answer the one he has proposed. In a system such as the one shown in his slides, would the dextro and levo isomers of potent sympathomimetic amines such as epinephrine have different solubilities and ionize to different degrees in the "sympathomimetic oil" postulated? I would like to comment briefly on Dr. Marrazzi's statements. The interrelationship between the actions of these sympathomimetic amines are undoubtedly complex. The substituents which are effective in increasing exicitatory action are also important for inhibitory action so that you have a melange of effects. However, I would like to emphasize the observation that it is not possible to elicit important inhibitory action in the absence of the alcoholic hydroxyl. Excitatory action is not similarly dependent upon this group. 'Epinine', N-methyl-p-(3, 4-di- hydroxyphenyl)ethylamine, is a potent pressor amine. On the other hand, this drug has little inhibitory action. The inhibitory action obtained may be non-specific inasmuch as papaverine has comparable potency. In conclusion, 1 believe that out of all this has emerged some indication as to the structural requirements important for excitatory and inhibitory sympathomimetic actions.