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APPENDIX L S. rRUCTURE-ACTIVITY RELAT TONS OF THE CENTRALLY ACTIVE ANTICHOLINERGIC AGENTS by Leo G. Abood, Ph.~. * The structure-ac~civi ty relationships of a large number and variety of anticholinergice have been described in several reviews (~-3), and only the general features will be described here. The main difficulty in comparing chemical structure with psychopharmacologic potency in that unequivocal behavioral measurements of potency are deficient. Although some anticholinergics have been evaluated for their paychotomimetic potency in man (2,43, the comparisons are baset largely on a battery of psychopharmacologic measures in animals, including hyperactivity (5). swim maze (6), characteristic exploratory head movements (2), and operant conditioning (7-9). The limitations and reliability of there comparisons have been discussed elsewhere (3), and they do peneit generalizations concerning the relative ability of the anticholinergics to pratuce behavioral disturbances in animals fit may reflect psychotogenlc potency in man. Structural variations in the heterocyclic amino alcohol result in marked changes in potency; the most potent anricholinergic is 3-quinuclidinyl benzi}ate, with its rigi d conf ormation ~ Figure L-1) . With respect to the acid moiety of the anticholinergics, the following structure-acti~rity relationships are found: As R1 is increased from methyl to higher alkyls or becomes hydrogen ~ alkenyl ~ amino ~ or aminoalkyl ~ psycho tropic potency diminishes without much effect on peripheral anticholinergic action. R2 should be an unsub&titutet phenyl group, wherase R3 must be either a cycloalkyl, alkynyl, thieny1, or unsubstituted phenyl. Alky1, aryl, halide, or hydroxyl subetituents on the phenyl rings abolish central action and diminish anticholinergic potency. R: and R3 can also be replaced by hexahydrofluorenyl (lO). O As "a" ts increased beyond 2 or "Y" beyond zero, psychotropic, but not anticholinergic, potency decreases. The position of the ester side chain affects central, but not peripheral action, with the 4-piperidyl ester -being most potent, the 3-ester second most and the 2-ester least. o R4 must be a hydroxyl group, whereas compounds with hydrogen or an isosteric methyl group are devoid of central action and have diminished anticholinergic action. If R4 is hydrogen and the hydroxy! group is present on phenol, central potency is retained. The duration of the psychotropic action of the Parlous antlcholiner'8ics depends both on the type of heterocycilc ammo *Professor, Center for Brain Research, University of Rochester School of Medicine ant Dentists, Rochester, New York 14642. L 1

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group and on R: and R3. The quinuclitInyl and pyrrolidyl amino derivatives tend to be longer-acting than piperidyl, tropanyl, or granatonyl; a cycloalkyl group in R2 or R3 prolongs duration. An alkynyl group in R: or Rat decreases duration, whereas increasing chain length or branching of the alkynyl group correspondingly increases duration. STEREOSPECIFICITY The anticholinergic glycolate esters of heterocyclic amino alcohols, including scopolamine and relates natural alkaloids, exist as optical isomers, resulting from the asymmetric C of both the amino alcohol and acid moiety. Of the two enantiomers of 3-diphenylacetyl quinuclidine, the (-) isomer had 25 times the antispasmodic potency of the (+) isomer; however, the isomers were of equal toxicity, whereas no difference in antispasmodic potency was noted between the two isomers of the quaternary derivative of 3-quinuclitinyl benzilate (11). With respect to their central action, the (+) and (-) enantiomers, which were prepared from the respective quinuclidinols resolved with (+)-camphor-10-sulfonic acid (11), differ markedly in potency (12,13). The (-) isomer was reported to have about 20 elmes the potency of the (+) isomer tn producing ataxia in togs (12); however, with the use of more elaborate behavioral measurements in cats, the potency difference was in excess of 100-fold (13). It is conceivable that the (I) isomer of 3-quinuclidinyl benzilate is devoid of activity on the central nervous system, ant the slight activity observed may be attributed to a 1: contamination by the (-) isomer. COMPARISON OF ~I~ ED ~ DATA WITH VARIOUS ~ICHOLINERGIC DRUGS In general, there is good agreement between the relative pharmacologic potency of various anticholinergic psychotomimetic agents in animals and that in humans. The comparison is applicable to both central and peripheral effects of the anticholinergics and to their duration of action. Table L-1 summarizes the data obtainer on the Edgewood volunteers who were given a single dose of an anticholinergic agent. Central nervous system (CNS) potency and peripheral antimuacarinic potency are expresses on an arbitrary Scale of 0-10, with 10 being the moat potent. Moat of the agent a used were of comparable peripheral antimuacarinic potency, whereas the CNS potency extended over the whole range. The CNS data in Table L-1 can be summarized as follows. BZ and other quinuclidinyl glycolatea containing at least one phenyl and a cycloalkyl group in the acid moiety were the most potent and had the greatest duration of action. The corresponding piperidyl glycolates were one-fifth to one-half as active as the quinuclidinyl esters. It can be concluded from such atructure-activity studies, which are based on extensive psychopharmacologic atests in both animals and human volunteers, that BZ ts the most representative of the most potent anticholinergica. However, atropine and methylaeropine are the most representative of the relatively inactive anticholinergics and could Serve as control drugs, particularly because atropine is equipotent, although of shorter duration, to BZ in peripheral anticholinergic effects. L 2

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SITES OF ANTICHOLIlYERGIC ACTION IN BRAIN . . Studies have been performed on the regional and cytoplasmic distribution of high-affinity radiolabeled anticholinergica in mammalian brain (14,15). In monkey brain, the regional distribution of 13H]3-quinuclitinyl benzilate wee found to correlate well with other cholinergic measures, such as 13H3choline uptake, choline acetyltransferase, and acetylcholinesterase (16). By far the highest level of all four parameters was in the putamen and caudate nucleus. The cerebral hemispheres, amygdala, and hippocampua contained about half the concentration of the benzilate, but the other concentrations were small fractions of those in the caudate nucleus. Apart from the caudate nucleus, the correlation between the distribution of the anticholinergics and the measures of cholinergic function was not impressive. By determining the extent to which [3H]3-quinuclidinyl benzilate binding was diminished by pretreatment of rats with atropine, the degree of specific binding of the anticholinergic can be determined in various brain areas (16~. It appears that, although a correlation was found in some brain areas (e.g., the caudate nucleus,) between the distribution of the anticholinergics and other measures of cholinergic action, the binding studies do not permit the conclusion that the drugs' distribution is an accurate reflection of the pattern of muscarinic cholinergic receptors in brain. The binding of f 3H]-anticho~ inergics to tissue preparations after lesion are produced in specific brain areas t~ another means of measuring specific receptors for the anticholinergics. If nerve t erminaLe of the cholinergic aff events to the hippocampus contain muscarinic cholinergic receptors, as suggested by pharmacologic studies (17,18), then lesions in the septal-hippocampal cholinergic tract should reduce the drugs' bindis~g--a conclusion that was experimentally verified ( 19~ . COMPETITION BE PREEN BEHAV IORAL POTENCY AND RECEPTOR AFFINITY To determine whe the r the centrally active anticholinergica bind to a physiologic receptor, an attempt was made to correlate inhibition binding constants of the various anticholinergic agents with their psychopharmacologic potency (20~. Such a correlation between behavioral and binding data has been attempted with a series of 14 glycolate esters (Figure 2~. ~ linear relation was observed between the behavioral data and the logarithm of the inhibition constants for binding. The behavioral data were taken from previously publishes accounts and are expressed quantitatively as BDI ~ behavioral disturbance index, or BD! (21) . From the evidence presented in this study, it can be concluded that [383quinuclidinyl benzilate binds to a muscarinic site in brain that is involved in producing the behavioral disturbances elicited by the glycolare esters. This conclusion is based on the low Kd, the saturability and stereospecificity of binding competition studies, and especially the reasonable correlation observed between behavioral and binding data ~ Figure 2) . Although the correlation can be useful in predicting the behavioral potency of new glycolate esters, on the basis of their inhibition constants, there are L 3

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notable exceptions, such as atropine, acopolamlne, ant compound IV. All three drugs had very high affinities for the 138] quinuclidinyl benzilate binding site, but their behavioral potencies were relativey low. They all contain heterocycllc ring systems other than piperldine or quinuclldlne. In a previous study, In an attempt to correlate the behavioral potencies of a series of glycolatea with some physical conatanta, the correlation tended to be excellent for the quinuclidinyl ant plperidyl esters, but not for those hating other heterocyclic amino rings, such as tropanol and granatonol. However, an excellent correlation was observer between at finity constants and.the ability of the anticholinergice to block the acetylcholine~intuced contraction of 1 leum, the corre ration being independent of the type of heterocycllc amino ring (20). A comparison of the receptor blading affinities of the two optical isomers of 3~qulnuclidinyl bensllate reveals that the (-) isomer has about SO times the affinity of the (+) isomer for a synaptlc~membrane preparation from rat caudate nucleus (unpublished). It hat been reported that the (-) isomer had only 20 times the affinity of the (+) lacer for a neural~embrane preparation from whole rat brain (203. The reasons for the difference may be that cautate nucleus contains a greater concentration of cholinergic receptors ant that a purifier synaptic membrane preparation was used in the later atuty. The relative bintlug affinities of the two isomers however, still had lesa than the 200:1 potency ratio fount in the cat behavioral teat (22) . A plausible explanation is that the specific neurons associated with the behavioral tiaturbances of the Rouge Tesy have a greater degree of binding stereospeciflcity than that exhibiter by membrane preparations from either whole brain or caudate nucleus. L 4

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REFERENCES . 1. Biel, J.H. ~ Abood, L.G. ~ Hoya, W.K. ~ Leiser, H.A. ~ Nuhfer, P.A., Klucheaky, E.F. 1961: Central atio~ulants II cholinergic blockade. J. Org. Chem. 26, 4096-4103. 2. Abood, L.G. ~ Biel, J.H. 1962: -~' ' agent e. Int. Rev. Neurobiol. 4, 218-271. anc ~cno tt nerg ic - psycho e omime ~ ic 3. Abood , L. G .: -1968 : The psychotomimetic glycolate estera. In: Drugs affecting the centralnervous system. Burger, A. (ed.), pp. 127-165. New Yoric: Dekker. 4. Gershon , S .: 1966: Behavioral effects of anti cholinergic psychotomimetics and their antogonism in man and animale. Recent . Adv. Biol. Psychiatr, 8, 141-1490. 5. 6. Lipman, tr., Aboot, L.G., Shurrager, P.S. : 1963: Effect of anticholinergic psychotomimetic agento on motor activity and body temperature. Arch. Int. Phar~acocodyn. Therap. 146, 174-191. Kosman, M.E.: 1964: Effects of amphetamine on the learnin8 and performance of mice in a sWIming maze. Proc. Soc. Exp. Biol. Iled . 115, 728-7 31. Polidora, ~1.: 1963: A sequential response methot for studyin8 complex behavior in animals and its application to the measurement of drug effects. J. Exp. Anal. Behav. 6, 271-277. 8. Weiss , B., Heller, A.: 1969: Methodological problems in evalutlng the role of cholinergic mechanisme in behavior. Fed. Proc. 28 :135-145. 9. Lowy, K., Weiss, B., Abood, L.G. 1974: Influence of an anticholinergic psychotomimetic agent on behavior in cats controlled by an auditory atimulus. Neurophsmacology 13, 70 7-718. 10. Freiter, E.R., Cannon, J.G., llilne, L.D., Abood, L.G. 1968: Synthesis of compounds with potential psychotomimetic activity. J. Het. Chem. II 1041-1045. Il. Sterobach, L.H., Kaiser, S.: 1952: Antispasmodics. lI. Es ters of basic bicyclic alcohola. J. Am. Chem. Soc . 74, 2219-2221. 12. Meyerhoffer, A.: 1971: Absolute conflgueratlon of 3~quinuclidinyl benzilate and the behavioral effect in dog of the optical isomers. J. Med. Chem. I5, 994-9 95. Lowy, K., Abood, L.G., Raines, lI.: 1976: Beha~rioral effect~ and binding affinities of two stereoisomeric p~ychotomimetic glycolates. ~r. Neuroaci, Res. 2, 157-165. L 5

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14. Abood, L.G., Rinalti, F.: 1959: Stutles with a tritium-labeled psychotomimetic agent. Paychophan~acology I, 117-1123. 15. Yamamura, H.L., Kuhar. M.JaKe ~ Greenberg, O. , Snyder, S.H. 1974: Muscarinic cholinergic receptor binting regional ti~tributioc in monkey brain. Brain Res. 66, 541-546. 16. Yamamura, H.~., Kuhar, M.J., S~yder, SeHo. 1974 In vivo itentification of muscarinic cholinergic receptor binding in rat brain. Brain Res. 80O9 i700176. 70 Molenar, P.C., Polak, P.L.: 1970: Stimulation by atropine of acetylcholine release and synehests in cortical slices from rat brain. Br. J. Pharmacol. 40, 606-417. 18. Szerb, J.C., Somogyi, G.T.: 1973: Depression of acetylcholine release from cerebral cortical slices by cholinesterase inhibition and oxotremorine. Nature (New Biol.) 241-121-122. 19. Yamamura, H.L., Snyter. S.H. 1974: Postaynaptic localization of muscarinic cholinergic receptor binding in rat hippocampus. Brain Res. 7B, 320~3260 - 20. Baumgold, J., Aboot, L.G., Aronstam, R.: 1977: Studies on the relationship of binting affinity to psychoactive ant anticholinergic potency of a group of psychotomimeeic glycolates. 8rain Res. 126, 331-340. 21. Gabel, N., Aboot, L.G.: 1965: Stereochemical factors related to the potency of anticholinergic psychotomimetic bugs. J. Het. Chem. 8, 616-619. 22. Lowy, K., Abood, M.E., Orexier, H., Abood, L.~. 1976: Antagon1am by cholinergic drugs of behavioral effects tn cats of an anticholinerglc paychotomimetic drug and enhancement by nicotine. ^urophermacology 16, 399-403 L 6

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T"LE 1 S true tur~h: t 1~t ty Dat ~ on "tl choline rgic ~ in Bu~n Volunte er Cod BZ 229608 EA 316 7 301,060 CS 2 7349 302,282 EA 3580 EA 344 3 302,196 Scopolamine 302,537 Di tran EA 3P'S 302, 668 At ropine Benaceyzice Me thylecopolamine He thyl a tropine 302,368 At ropine+benac tyzine Dose Duration of Potency. No. u~J4g Effect, ~ Peri~here1 CNS Su ~ects 5-8 48-96 10 10 354 1-2 48-72 10 10 21 3-4 48-120 10 10 24 3-5 48-120 10 9 29 7-8 6-24 10 S 50 7-14 6~12 10 4 8 4-37 4-60 22-54 6-24 6~12 -12-48 24-48 4-10 6-16 6-24 4-6 6-24 100 12-24 3-24 12-24 13-18 12-48 1-70 12-26 100 6-26 1-30 6-30 2-20 6-48 3-4 6-24 (100+20) 4-10 10 10 10 10 8 8 8 10 10 10 9 8 10 6 S 8 10 10 9 4 3 4 l o o 1 3 136 3 101 56 637 18 12 171 8 39 602 17 66 1S 10 aPotency 18 expressed in tens of peripheral (mydrisata, dryness of mouth, etc.) and central nervoua ayatem (CNS) effects. The latter involve confualon, hallucinatlona, aemory loca, and delirtum. Oruge are e~raluated relative to BZ. L 7

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Figure F-1 Chemical structure of various heterocyclic amino esters of benzilic acid. I ~ 3~quinuclidinyl, II ~ N~ethy1-4-piperidyl, II! N-methyI-3-piperidyl, IV ~ N~ethyl-3-pyrrolidy1, V ~ Nose thyl-N - ethyI-2, 3-piperidienyl, VI - 1,2, 2, 6-eeeramethylpiperidyl, VII - N-methyI-3-eropanyl' VIII - ti-methyl-3-granatonyl, IX - l~yrrolizidinyl9 X - 1,2,2,6,6-pent~ethyl-3-piperldyl. R - benzilate. Psychotomimetic potency decreases from ~ to X. 1 N~ NACHO 11 8~1 IV V V1 ' V] 1 *' CH3 ~ OR :: CH Calf,: stir L 8

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Figure F-2 Correlation of bindlog afflaity of various centrally ctlve antichollnergice to their behavlore1 disturbance index (BDI). Bindi fflnlty is measured by Hi, the drug concentration protuclDg 5C: Dg lahibition of t H] quInuclidinyl benzilate bindiDg to breln~embrane preparationa BDI - compoalte lcdex of behavlore1 neasurasents in Bvarlou1 anl~la as a olesaure of paychotroplc potency D t d .1 _ 1 y ~' - '1~ l ~' 1 ~ 111 fil ~ . ' ?~< ' Qi~ ~. aCo~ ~ ~ ~ ~v _' .~ -. ~ ~ , ~ ~ ~ ~. . t , ~ ~ 60~ ~, !. ~0 0h ~ xl,~ -100e slv X11 a - .~ OC<~, ~.~ ~ ~ ac" f-. ~ 0~ BD' L 9

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