Lesopitron Dihydrochloride

Lesopitron acts as a ligand for central serotonin 5-HT_1A receptors. K_i obtained from [³H]8-OH-DPAT competition studies was 104.8 ± 10.6 nmol/l. As lesopitron did not affect the binding of [³H]paroxetine, involvement of the serotonin reuptake system in the effects of lesopitron is rejected. Lesopitron inhibits haloperidol-induced catalepsy that is the consequence of its action on 5-HT_1A autoreceptors. The ability of lesopitron to induce 5-HT syndrome reflects post-synaptic 5-HT_1A receptor activation and the reversion of 8-OHDPAT-induced 5-HT syndrome by lesopitron suggests a partial agonist effect on this receptor-type. Lesopitron induced a hypothermic effect due to the enhanced activation of post-synaptic 5-HT_1A receptors. The agonist effect of lesopitron on 5-HT_1A receptors and its marked hypothermic effect is an added value for this drug and a stimulus to the study of its possible neuroprotective action.

Lesopitron is an anxiolytic with pre- and post-synaptic 5-HT1A agonist activity, which is under development by Esteve [172924, 175197]. It is in phase II trials in Spain [391567, 396196] and the US [396174, 396196]. A series of pilot studies in other indications are also under way [396196]. In phase I trials in healthy volunteers, lesopitron was well tolerated in single doses up to 50 mg, and up to 45 mg/day in repeated doses [234400]. Lesopitron has negligible effects on alpha-adrenergic and dopaminergic receptors [162653], and was more potent than structurally-related 5-HT1A agonists in rat social interaction and marmoset anxiety models. It also countered benzodiazepine withdrawal-induced anxiety in rodents [232978]. The acute toxicity of lesopitron is low and it does not potentiate the effects of alcohol or barbiturates. Long-term usage led to reductions in plasma glucose, triglycerides, phospholipids and cholesterol [232984]. Lesopitron was being developed in collaboration with Knoll Pharmaceuticals [172924, 175197] but this agreement was terminated in December 1995 [394772].