title: 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.
abstract: 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.
authors.affiliation: Wyeth, Neuroscience Discovery Research, Princeton, NJ 08543, USA. schechl@wyeth.com
authors.forename: L E
authors.initials: LE
authors.lastname: Schechter
authors.forename: D L
authors.initials: DL
authors.lastname: Smith
authors.forename: S
authors.initials: S
authors.lastname: Rosenzweig-Lipson
authors.forename: S J
authors.initials: SJ
authors.lastname: Sukoff
authors.forename: L A
authors.initials: LA
authors.lastname: Dawson
authors.forename: K
authors.initials: K
authors.lastname: Marquis
authors.forename: D
authors.initials: D
authors.lastname: Jones
authors.forename: M
authors.initials: M
authors.lastname: Piesla
authors.forename: T
authors.initials: T
authors.lastname: Andree
authors.forename: S
authors.initials: S
authors.lastname: Nawoschik
authors.forename: J A
authors.initials: JA
authors.lastname: Harder
authors.forename: M D
authors.initials: MD
authors.lastname: Womack
authors.forename: J
authors.initials: J
authors.lastname: Buccafusco
authors.forename: A V
authors.initials: AV
authors.lastname: Terry
authors.forename: B
authors.initials: B
authors.lastname: Hoebel
authors.forename: P
authors.initials: P
authors.lastname: Rada
authors.forename: M
authors.initials: M
authors.lastname: Kelly
authors.forename: M
authors.initials: M
authors.lastname: Abou-Gharbia
authors.forename: J E
authors.initials: JE
authors.lastname: Barrett
authors.forename: W
authors.initials: W
authors.lastname: Childers
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D002144:Callithrix; D003071:Cognition / Q000187:drug effects*; D010856:Columbidae; D004146:Dioxanes / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D008732:Methoxydimethyltryptamines / Q000037:antagonists & inhibitors; D017551:Microdialysis; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012453:Saimiri; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: D004146:Dioxanes; D008732:Methoxydimethyltryptamines; D010879:Piperazines; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D018698:Glutamic Acid; C500836:lecozotan; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000109:Acetylcholine