Assessment of the neuroleptic potential of some novel benzamide, butyrophenone, phenothiazine and indole derivatives

Abstract

Abstract A series of experimental models were used to determine the activity spectra of potential neuroleptic agents on extrapyramidal and/or mesolimbic dopamine systems: catalepsy induction by the drug alone or in the presence of the acetylcholine-like agent, RS86 [spiro-(N'-methylpiperidyl-4′)-N-ethyl succinamide hydrogen fumarate], or α-methyl-p-tyrosine (α-MT), stereotypy antagonism (amphetamine) and hyperactivity antagonism (intra-accumbens and intrastriatal dopamine). Antiemetic potential was also considered. Whilst classical neuroleptics were active in all test situations, other neuroleptics including benzamide, phenothiazine, butyrophenone and indole derivatives exhibited novel activity spectra: clozapine failed to interact with α-MT, metoclopramide failed to antagonize a mesolimbic hyperactivity or interact with the acetylcholine-like agent. Other benzamide derivatives, clebopride, AHR6092, sultopride and tiapride also failed to interact with RS86, but whilst clebopride was active in all other test situations, AHR6092 was inactive in all but the antiemetic test, sultopride was only weakly cataleptogenic and tiapride only antagonized stereotypy and hyperactivity from the striatum. AHR6839, AHR6134, AHR6645, AHR6505B and AHR1709 were generally inactive in the catalepsy tests but exerted dopamine antagonistic potential in other test procedures. The antagonistic ability of AHR1709 was only revealed in the tests where dopamine function was specifically raised in the nucleus accumbens and caudate-putamen by intracerebral dopamine injections. Data are discussed in terms of a dissociation of drug effects on different cerebral dopamine systems.