The neuropharmacological profile of tefludazine, a potential antipsychotic drug with dopamine and serotonin receptor antagonistic effects

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Abstract
The neuropharmacology of tefludazine, a new neuroleptic with phenylindan structure, has been investigated in comparison with cis(Z)‐flupentixol, fluphenazine, haloperidol, methiothepin, thioridazine, and clozapine. Tefludazine showed potent dopamine (DA) antagonistic activity in a broad range of test models in vitro and in vivo in mice, rats, and dogs (receptor binding, antagonism of DA agonist‐induced behavior, inhibition of conditioned avoidance, catalepsy, etc.). High oral activity and long duration of action was found. Interestingly, the cataleptogenic potency at the time of peak effect was seven times weaker than the antistereotypic activity, in contrast with that observed with cis(Z)‐flupentixol, fluphenazine, and haloperidol. In addition to DA antagonism, tefludazine was equipotent at 5‐HT receptors (in vitro receptor binding, 5‐HT antagonism in isolated peripheral tissue, cardiovascular 5‐HT antagonism, antagonism of I‐5‐HTP‐ and 5‐MeODMT‐induced behaviors). No antimuscarinic and low α‐adrenoceptor blocking effect was found in pithed rats and in denervated cat nictitating membrane preparation. The DA/5‐HT activity profile of tefludazine resembled that of methiothepin, which, however, had potent α‐adrenoceptor blocking effect. It is concluded that tefludazine has a neuropharmacological profile that should combine antipsychotic potential with lower risk of extrapyramidal symptoms.