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.