Molecular Pharmacology, Vol 10, 759-766, Copyright © 1974 by the American Society for Pharmacology and Experimental Therapeutics

The Action of Neuroleptic Drugs on Dopamine-Stimulated Adenosine Cyclic 3',5'-Monophosphate Production in Rat Neostriatum and Limbic Forebrain

¹ Medical Research Council Neurochemical Pharmacology Unit, Department of Pharmacology, Medical School, Cambridge CB2 2QD, England

Neuroleptic drugs of various types were more potent inhibitors of dopamine-sensitive production of adenosine cyclic 3',5'-monophosphate in homogenates of rat brain striatum than non-neuroleptic drugs of similar structures. The most potent drugs were phenothiazines and thioxanthenes with a -CF₃ group in position 2 of the tricyclic system and a piperazino side chain. There were also large differences in the effects of cis and trans isomers of thioxanthenes in which the 2-substituent and the side chain are on the same or opposite side of the double bond connecting the side chain to the ring system. Thus -flupenthixol, -clopenthixol, and -chlorprothixene, which are the cis isomers, were considerably more potent than the corresponding -isomers of the same drugs. -Flupenthixol was also considerably more potent than the -isomer in antagonizing the effect of dopamine on cyclic AMP production in the olfactory tubercle and nucleus accumbens, and in antagonizing the potent dopamine agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene in the striatum. These results are discussed in relation to the hypothesis that neuroleptic activity may be related to the blockade of dopamine receptors in the central nervous system.

Note:
ACKNOWLEDGMENTS We thank Dr. I. Møller-Nielsen of Lundbeck, Ltd., for supplies of thioxanthene isomers. Other drugs used in this study were kindly provided by Sandoz, Ltd., May and Baker, Ltd., Wander, Ltd., and Janssen Pharmaceutica. 2-Amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene was a gift from Dr. R. Pinder of the Chemical Defence Establishment, Porton Down, Salisbury, Wiltshire.

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