Aminoalkylindoles: atypical dopamine antagonists

Abstract

Abstract The neuropharmacological profile of a series of aminoalkylindole compounds (AHR-1229-(3-[2-(3-indolyl)-ethyl]-butylamino-1-phenyl-pyrrolidine), AHR1771-(1-[2-(2-methyl-3-indolyl)ethyl]-4-phenyl-3,4-dehydropiperidine), AHR1806-(1-[2-(5-chloro-3-indolyl)-ethyl]-4-phenyl-3,4-dehydropiperidine), AHR1858-(1-[2-(3-indolyl)ethyl]-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine), AHR1859-(1-[2-(1-methyl-3-indolyl)ethyl]-4-phenyl-1,2,3,6-tetrahydropyridine), AHR1709-(1-[2-(3-indolyl)ethyl]-4-phenyl-1,2,3,6-tetrahydropyridine) was determined in comparison with the classical neuroleptic agents haloperidol and oxypertine, the latter being of similar indole structure. The indole analogues were shown to antagonize amphetamine-induced toxicity in aggregated mice, to indicate a ‘tranquillizing’ action but, in contrast to haloperidol and oxypertine, showed weak or no activity in other classical behavioural tests for neuroleptic action, catalepsy induction and stereotypy antagonism. In further contrast to haloperidol or oxypertine, the indole derivatives failed to displace [3H]spiperone in radioligand binding assays and failed to increase prolactin levels. However, similarly to both typical and atypical neuroleptic agents, the indole derivatives were shown to inhibit the behavioural hyperactivity resulting from the intracerebral administration of dopamine into the mesolimbic nucleus accumbens of rat. The dissociation of an ability to antagonize a dopamine action in the mesolimbic system from classical neuroleptic actions involving other cerebral dopamine systems is the most important finding of the present study.