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NEUROPHARMACOLOGY

Lecozotan (SRA-333): A Selective Serotonin 1A Receptor Antagonist That Enhances the Stimulated Release of Glutamate and Acetylcholine in the Hippocampus and Possesses Cognitive-Enhancing Properties

Wyeth, Neuroscience Discovery Research, Princeton, New Jersey (L.E.S., D.L.S., S.R.-L., S.J.S., L.A.D., K.M., D.J., M.P., T.A., S.N., J.E.B.); School of Pharmacy, University of Bradford, Bradford, West Yorkshire, United Kingdom (J.A.H., M.D.W.); Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Medical College of Georgia, Augusta, Georgia (J.B., A.V.T.); Princeton University; Princeton, New Jersey (B.H., P.R.); and Wyeth, Chemical and Screening Sciences, Princeton, New Jersey (M.K., M.A.-G., W.C.)

Recent data has suggested that the 5-hydroxytryptamine (5-HT)_1A receptor is involved in cognitive processing. A novel 5-HT_1A receptor antagonist, 4-cyano-N-{2R-[4-(2,3-dihydrobenzo[1,4]-dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide HCl (lecozotan), which has been characterized in multiple in vitro and in vivo pharmacological 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-HT_1A receptor antagonist. Using in vivo microdialysis, lecozotan (0.3 mg/kg s.c.) antagonized the decrease in hippocampal extracellular 5-HT induced by a challenge dose (0.3 mg/kg s.c.) of 8-hydroxy-2-dipropylaminotetralin (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-HT_1A receptor tolerance or desensitization in a behavioral model indicative of 5-HT_1A receptor function. In drug discrimination studies, lecozotan (0.01–1 mg/kg i.m.) did not substitute for 8-OH-DPAT and produced a dose-related blockade of the 5-HT_1A agonist discriminative stimulus cue. In aged rhesus monkeys, lecozotan produced a significant improvement in task performance efficiency at an optimal dose (1 mg/kg p.o.). Learning deficits induced by the glutamatergic antagonist MK-801 [(-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] (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 i.m.) 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 Alzheimer's disease.

Address correspondence to: Dr. Lee Schechter, Neuroscience Discovery, Wyeth Research, Princeton, NJ 08543. E-mail: schechl{at}wyeth.com

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