SAM-531, N,N-dimethyl-3-{[3-(1-naphthylsulfonyl)-1H-indazol-5-yl]oxy} propan-1-amine, a novel serotonin-6 receptor antagonist with preclinical pro-cognitive efficacy

The 5-HT6 receptor (5-HT6R) is a G-protein coupled receptor positively coupled to adenylate cyclase primarily localized within the central nervous system, particularly in brain regions associated with cognition. Antagonism of the 5-HT6R has been reported to modulate the release of multiple neurotransmitters including elevating extracellular levels of glutamate and acetylcholine in regions associated with cognitive function such as the cerebral cortex and hippocampal formation. Accumulating preclinical and clinical data suggest that 5-HT6R antagonists may function to improve cognitive performance and therefore serve as effective treatment options for Alzheimer's disease. SAM-531 (WAY-262531) is a new chemical entity that is 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. 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. SAM-531 is a potent and selective full antagonist at the human 5-HT6R (Ki = 1.0 nM; IC50 = 10 nM). In rats, oral administration of SAM-531 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 SAM-531 enhanced retention of recognition memory when measured 48 hours after training, a time at which memory no longer can be measured in vehicle-treated animals. 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.