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

L. E. Schechter, D. L. Smith, S. Rosenzweig-Lipson, S. J. Sukoff, L. A. Dawson, K. Marquis, D. Jones, M. Piesla, T. Andree, S. Nawoschik, J. A. Harder, M. D. Womack, J. Buccafusco, A. V. Terry, B. Hoebel, P. Rada, M. Kelly, M. Abou-Gharbia, J. E. Barrett, W. Childers

Research output: Contribution to journalArticle

106 Scopus citations

Abstract

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-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-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.

Original languageEnglish (US)
Pages (from-to)1274-1289
Number of pages16
JournalJournal of Pharmacology and Experimental Therapeutics
Volume314
Issue number3
DOIs
StatePublished - Sep 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Schechter, L. E., Smith, D. L., Rosenzweig-Lipson, S., Sukoff, S. J., Dawson, L. A., Marquis, K., Jones, D., Piesla, M., Andree, T., Nawoschik, S., Harder, J. A., Womack, M. D., Buccafusco, J., Terry, A. V., Hoebel, B., Rada, P., Kelly, M., Abou-Gharbia, M., Barrett, J. E., & Childers, W. (2005). 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. Journal of Pharmacology and Experimental Therapeutics, 314(3), 1274-1289. https://doi.org/10.1124/jpet.105.086363