Lecozotan (SRA-333): a selective serotonin1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties.

Abstract

Recent data has suggested that the 5-HT1A receptor is involved in cognitive processing. A novel 5- HT1A receptor antagonist, 4-cyano-N- [(2R)-[4- (2,3-dihydrobenzo [1,4] dioxin-5-yl) piperazin-1-yl] propyl]-N-pyridin-2-yl-benzamide hydrochloride (lecozotan), which has been characterized in multiple in vitro and in vivo pharmacologic assays as a drug to treat cognitive dysfunction, is reported. In vitro binding and intrinsic activity determinations demonstrated that lecozotan is a potent and selective 5-HT1A receptor antagonist. Using in vivo microdialysis, lecozotan (0.3 mg/kg sc) antagonized the decrease in hippocampal extracellular 5-HT induced by a challenge dose (0.3 mg/kg sc) of 8 OH-DPAT and had no effects alone at doses 10-fold higher. Lecozotan significantly potentiated the potassium chloride-stimulated release of glutamate and acetylcholine in the dentate gyrus of the hippocampus. Chronic administration of lecozotan did not induce 5-HT1A receptor tolerance or desensitization in a behavioral model indicative of 5- HT1A receptor function. In drug discrimination studies, lecozotan (0.01-1 mg/kg im) did not substitute for 8-OH-DPAT and produced a dose-related blockade of the 5-HT1A agonist discriminative stimulus cue. In aged rhesus monkeys, lecozotan produced a significant improvement in task performance efficiency at an optimal dose (1 mg/kg po). Learning deficits induced by the glutamatergic antagonist MK-801 (assessed by perceptually complex and visual spatial discrimination) and by specific cholinergic lesions of the hippocampus (assessed by visual spatial discrimination) were reversed by lecozotan (2 mg/kg im) in marmosets. The heterosynaptic nature of the effects of lecozotan imbues this compound with a novel mechanism of action directed at the biochemical pathologies underlying cognitive loss in AD.