Jpet #86363 1 Lecozotan (sra-333): a Selective Serotonin1a Receptor Antagonist That Enhances the Stimulated Release of Glutamate and Acetylcholine in the Hippocampus and Possesses

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) piperazin1-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 5HT1A 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. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on June 10, 2005 as DOI: 10.1124/jpet.105.086363 at A PE T Jornals on A ril 9, 2017 jpet.asjournals.org D ow nladed from