NEUROCHEMICAL AND INVIVO PHARMACOLOGICAL PROFILE OF SERTINDOLE, A LIMBIC-SELECTIVE NEUROLEPTIC COMPOUND

Sertindole (5-chloro-1-(4-fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-4-piperidyl]-1H-indole) is a new neuroleptic with a very high selectivity for dopamine (DA) neurones in the ventral tegmental area compared to DA neurones in substantis nigra pars compacta (Skarsfeldt, T., and Perregaard, J. Eur. J. Pharmacol. 182:613-614, 1990). Neurochemical and behavioural effects of sertindole have been investigated in comparison with the classical neuroleptics haloperidol and fluphenazine and the atypical neuroleptic clozapine. In vitro sertindole has high affinity for serotonin S2 (5-HT2) receptors, DA D-2 receptors, and alpha-1-adrenoceptors; moderate affinity for DA D-1 receptors; low affinity for alpha-2-adrenoceptors, histamine H-1 receptors and sigma receptors; and no affinity for 5-HT1A, muscarine cholinergic receptors, and beta-adrenoceptors. The in vivo pharmacology is atypical, i.e., a remarkably weak or no effect in acut tests for DA antagonism, and the cataleptogenic potential is very low. Sertindole shows a very potent and long-acting antagonism at central as well as peripheral 5-HT2 receptors. The antagonistic effect at peripheral alpha-1-adrenoceptors is relatively weak in comparison with the 5-HT2 antagonistic potency in vivo and in vitro. Sertindole shows no anticholinergic effects. In conclusion the pharmacological profile suggests that sertindole is an atypical neuroleptic compound with a low potential for extrapyramidal, autonomic, and anticholinergic side effects.