PT  - JOURNAL ARTICLE
AU  - L. E. Schechter
AU  - D. L. Smith
AU  - S. Rosenzweig-Lipson
AU  - S. J. Sukoff
AU  - L. A. Dawson
AU  - K. Marquis
AU  - D. Jones
AU  - M. Piesla
AU  - T. Andree
AU  - S. Nawoschik
AU  - J. A. Harder
AU  - M. D. Womack
AU  - J. Buccafusco
AU  - A. V. Terry
AU  - B. Hoebel
AU  - P. Rada
AU  - M. Kelly
AU  - M. Abou-Gharbia
AU  - J. E. Barrett
AU  - W. Childers
TI  - 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
AID  - 10.1124/jpet.105.086363
DP  - 2005 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1274--1289
VI  - 314
IP  - 3
4099  - http://jpet.aspetjournals.org/content/314/3/1274.short
4100  - http://jpet.aspetjournals.org/content/314/3/1274.full
SO  - J Pharmacol Exp Ther2005 Sep 01; 314
AB  - Recent data has suggested that the 5-hydroxytryptamine (5-HT)1A 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 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-HT1A 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-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 i.m.) 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 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. The American Society for Pharmacology and Experimental Therapeutics