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

  1. L. E. Schechter,
  2. D. L. Smith,
  3. S. Rosenzweig-Lipson,
  4. S. J. Sukoff,
  5. L. A. Dawson1,
  6. K. Marquis,
  7. D. Jones,
  8. M. Piesla,
  9. T. Andree,
  10. S. Nawoschik,
  11. J. A. Harder,
  12. M. D. Womack,
  13. J. Buccafusco,
  14. A. V. Terry,
  15. B. Hoebel,
  16. P. Rada,
  17. M. Kelly2,
  18. M. Abou-Gharbia,
  19. J. E. Barrett3 and
  20. W. Childers
  1. 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.)
  1. Address correspondence to:
    Dr. Lee Schechter, Neuroscience Discovery, Wyeth Research, Princeton, NJ 08543. E-mail: schechl{at}wyeth.com

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-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.

Footnotes

  • This research was supported by Wyeth Research (Princeton, NJ and Collegeville, PA).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.105.086363.

  • ABBREVIATIONS: 5-HT, 5-hydroxytryptamine; 8-OH-DPAT, 8-hydroxy-2-dipropylaminotetralin; WAY-100135, N-tert-butyl-3-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylpropanamide; WAY-100635, [O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride; NAD-299, (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate; AD, Alzheimer's disease; NMDA, N-methyl-d-aspartate; SRA-333, 4-cyano-N-{2R-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide HCl (lecozotan); CHO, Chinese hamster ovary; DA, dopamine; GTPγS, guanosine 5′-O-(3-thio)triphosphate; aCSF, artificial cerebrospinal fluid; HPLC, high-performance liquid chromatography; ANOVA, analysis of variance; FR, fixed ratio; 5-MeODMT, 5-methoxy-dimethyltryptamine; DMTS, delayed matching-to-sample; MK-801, (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate; VBD, vertical diagonal band; WGTA, Wisconsin General Test Apparatus; DRN, dorsal raphe neuronal; CI, confidence interval; BMY-7378, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione; NAN-190, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine.

  • ↵1 Current address: Psychiatry Centre of Excellence, GlaxoSmithKline, New Frontiers Science Park, Harlow Essex, UK

  • ↵2 Current address: Renovis, South San Francisco, CA

  • ↵3 Current address: Adolor Corporation, Exton, PA

    • Received March 17, 2005.
    • Accepted June 9, 2005.
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  1. Published online before print June 10, 2005, doi: 10.1124/jpet.105.086363 JPET September 2005 vol. 314 no. 3 1274-1289
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