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, Alvin V Terry, B. Hoebel, P. Rada, M. Kelly, M. Abou-Gharbia, J. E. Barrett, W. Childers

Research output: Contribution to journalArticle

104 Citations (Scopus)

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 1 2005

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Serotonin Antagonists
Receptor, Serotonin, 5-HT1A
Acetylcholine
Glutamic Acid
Hippocampus
Serotonin 5-HT1 Receptor Antagonists
8-Hydroxy-2-(di-n-propylamino)tetralin
Serotonin 5-HT1 Receptor Agonists
lecozotan
Callithrix
Parahippocampal Gyrus
Imines
Dizocilpine Maleate
Potassium Chloride
Dentate Gyrus
Microdialysis
Task Performance and Analysis
Macaca mulatta
Pharmaceutical Preparations
Cholinergic Agents

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

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. / 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, Alvin V; Hoebel, B.; Rada, P.; Kelly, M.; Abou-Gharbia, M.; Barrett, J. E.; Childers, W.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 314, No. 3, 01.09.2005, p. 1274-1289.

Research output: Contribution to journalArticle

Schechter, LE, Smith, DL, Rosenzweig-Lipson, S, Sukoff, SJ, Dawson, LA, Marquis, K, Jones, D, Piesla, M, Andree, T, Nawoschik, S, Harder, JA, Womack, MD, Buccafusco, J, Terry, AV, Hoebel, B, Rada, P, Kelly, M, Abou-Gharbia, M, Barrett, JE & 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, vol. 314, no. 3, pp. 1274-1289. https://doi.org/10.1124/jpet.105.086363
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, Alvin V ; Hoebel, B. ; Rada, P. ; Kelly, M. ; Abou-Gharbia, M. ; Barrett, J. E. ; Childers, W. / 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. In: Journal of Pharmacology and Experimental Therapeutics. 2005 ; Vol. 314, No. 3. pp. 1274-1289.
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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.",
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T2 - A selective serotonin 1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties

AU - Schechter, L. E.

AU - Smith, D. L.

AU - Rosenzweig-Lipson, S.

AU - Sukoff, S. J.

AU - Dawson, L. A.

AU - Marquis, K.

AU - Jones, D.

AU - Piesla, M.

AU - Andree, T.

AU - Nawoschik, S.

AU - Harder, J. A.

AU - Womack, M. D.

AU - Buccafusco, J.

AU - Terry, Alvin V

AU - Hoebel, B.

AU - Rada, P.

AU - Kelly, M.

AU - Abou-Gharbia, M.

AU - Barrett, J. E.

AU - Childers, W.

PY - 2005/9/1

Y1 - 2005/9/1

N2 - 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.

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