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P3‐330: A novel cognitive enhancer, spiro[imidazo[1,2‐a]pyridine‐3,2‐indan]‐2(3H)‐one (ZSET1446), promotes hippocampal neurogenesis and ameliorates depressive behavior in olfactory bulbectomized mice
Author(s) -
Fukunaga Kohji,
Yamamoto Yui,
Moriguchi Shigeki,
Shioda Norifumi
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1831
Subject(s) - neurogenesis , dentate gyrus , mecamylamine , subgranular zone , hippocampus , tail suspension test , hippocampal formation , endocrinology , chemistry , medicine , pharmacology , neuroscience , behavioural despair test , psychology , nicotinic agonist , neural stem cell , biology , microbiology and biotechnology , receptor , antidepressant , subventricular zone , stem cell
a selective full antagonist at the 5-HT6R. Here we describe the pre-clinical profile of SAM-531 in support of its clinical development as a treatment for Alzheimer’s disease. Methods: SAM-531 was characterized in vitro in multiple assays evaluating binding affinity, functional activity and receptor selectivity. In vivo characterization of SAM-531 consisted of an evaluation of the effect of treatment on brain neurochemistry using in vivo microdialysis as well as tests of rodent cognitive function such as contextual fear conditioning and novel object recognition. Cognitive testing was performed in assays utilizing both pharmacological and non-pharmacological deficit states. Results: SAM-531 is a potent and selective full antagonist at the human 5HT6R (Ki 1⁄4 1.0 nM; IC50 1⁄4 10 nM). In rats, oral administration of SAM531 caused significant increases in extracellular levels of glutamate and acetylcholine in the dorsal hippocampus. Treatment with SAM-531 blocked a scopolamine-induced deficit in a hippocampal-dependent learning and memory task, contextual fear conditioning. In addition, SAM-531 treatment blocked both glutmatergic(MK-801) and cholinergic-mediated (scopolamine) deficits in recognition memory. Furthermore, treatment with SAM531 enhanced retention of recognition memory when measured 48 hours after training, a time at which memory no longer can be measured in vehicletreated animals. Conclusions: SAM-531 is a potent, selective and orally bioavailable 5-HT6R antagonist which modulates neurotransmitters associated with learning and memory and is active in multiple assays of cognitive dysfunction in the rodent. These studies provide pre-clinical support for the further development of the 5-HT6R antagonist SAM-531 as a potential treatment for Alzheimer’s disease.