First Symposium on Chemical-Biological Correlation, May 26-27, 1950 (1951) / Chapter Skim
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Review of the Structural Requirements for Sympathomimetic Drug Action
Review of the Structural Requirements for Sympathomimetic Drug Action
Pages 73-124
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From page 74... ...
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.
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From page 75... ...
Structure R Fressor Action Toxicit „ Ref. Animal Relative Potency Animal A.dmin mgm.
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From page 76... ...
Structure R Pressor Action^/ Toxicity Ref. Animal Relative Potency Animal Admin.
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From page 77... ...
The substitution of an alcoholic hydroxyl group at C-i of phenylalkylamines is generally unfavorable for vasopressor action (Table III)
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From page 78... ...
Structure X Y Pressor Action^/ Toxicity Ref. Animal Relative Potency Animal Admin.
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From page 79... ...
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)
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From page 80... ...
Animal Relative Potency Animal Admin mgm.
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From page 81... ...
Structure X Y Pressor Action Toxicity Ref. Animal Relative Animal Admin.
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From page 82... ...
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.
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From page 83... ...
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.
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From page 84... ...
. 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)
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From page 85... ...
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 vasopressor 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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From page 88... ...
It would appear that the 3-hydroxy group on the phenyl ring is the key structure for vasopressor action and that the alcoholic hydroxyl at C-2 is similarly the key structure for vasodepressor action. Other substitutions are important insofar as they modify these actions.
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From page 89... ...
Structure 43 X Y Pressor Action^/ Toxicitv Ref. Animal Relative Potency Animal Admin.
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From page 90... ...
Structure 4 3 2 Y Fressor Action^/ Toxicity Ref. Animal Relative Potency Animal Admin.
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From page 91... ...
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.
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From page 92... ...
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.
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From page 93... ...
Structure 4 R X Y Pre sor Action^ Toxicity Ref. Anima Relative Potency Animal Admin.
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From page 94... ...
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.
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From page 95... ...
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.
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From page 96... ...
, 115 t 11.6. Miscellaneous compounds, evaluated for vasopressor action, are shown in Table XVIII.
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From page 97... ...
/ Toxic ity Ref. Animal Relative Potency Animal Admin mgm, /kgm.
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From page 98... ...
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.
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From page 99... ...
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.
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From page 100... ...
Structure R X Y Bronchodilator Action Ref. Preparation Relative Potency^ 90 OH H H guinea pig (d,l)
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From page 101... ...
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.
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From page 102... ...
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)
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From page 103... ...
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)
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From page 104... ...
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.
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From page 105... ...
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.
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From page 106... ...
TABLE XXIV THE EFFECT OF SYMPATHOMIMETIC AMINES ON INTESTINAL MOTILITY CATECHOL DERIVATIVES Hy~\ lOf VCH. CHX-NHY Compound No.
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From page 107... ...
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.
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From page 108... ...
These data are shown in Table XXV. TABLE XXV STIMULATING ACTION OF SYMPATHOMIMETIC AMINES ON THE CENTRAL NERVOUS SYSTEM ' \ CH-X NHY R ComStructure 4 3 R X Y Central Nervous System Stimulation Ref.
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From page 109... ...
Structure 4 3 R X Y Central Nervous System Stimulation Ref. Animal Dose Used mgm.
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From page 110... ...
159) with the corresponding phenyl analog and found that hydrogenation of the ring greatly reduced excitatory action.
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From page 111... ...
Addition of the alcoholic hydroxyl increases greatly this inhibitory action. The primary amine, arterenol, may either contract or relax the guinea pig uterus?
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From page 112... ...
^ 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.
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From page 113... ...
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.
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From page 114... ...
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.
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From page 116... ...
, Die biogenen Amine und ihre Bedeutung fur die Physiologic und Pathologic des Pflanzlichen und tierischen Stoffwechsels, Nordeman, Karger, Basel (1940)
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From page 117... ...
117 54. Jacobsen.
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From page 118... ...
118 78. Marsh, D
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From page 119... ...
119 107. Trendelenburg, P., Handbuch der experimentellen Pharmakologie, Heffter, 2.
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From page 120... ...
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.
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From page 121... ...
curare, methacholine and atropine are inactive on triglyceride oil on which the sympathomimetic drugs generate potential (including the aliphatic members, octin, oenethyl and aranthol)
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From page 122... ...
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-phenylisopropylamine is the basic member of an analogous series)
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From page 123... ...
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.
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