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lecozotan is a drug that stimulates release of two nerve cell
communication chemicals called acetylcholine and glutamate, as a treatment
for mild to moderate Alzheimer's disease.
Lecozotan is not yet approved.
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Scientific Publications :
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J Pharmacol Exp Ther. 2005 Sep ;314:1274-89
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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.
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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
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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--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.
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