Novel 5-HT5A receptor antagonists ameliorate scopolamine-induced working memory deficit in mice and reference memory impairment in aged rats

Despite the human 5-ht5a receptor being cloned in 1994,the biological function of this receptor has not been extensively characterized due to a lack of specific ligands. we recently reported that the selective 5-ht5a receptor antagonist asp5736 ameliorated cognitive impairment in several animal models of schizophrenia. given that areas of the brain with high levels of 5-ht5a receptor expression,such as the hippocampus and cerebral cortex,have important functions in cognition and memory,we evaluated the chemically diverse,potent and brain-penetrating 5-ht5a receptor antagonists asp5736,as2030680,and as2674723 in rodent models of cognitive dysfunction associated with dementia. each of these compounds exhibited a high affinity for recombinant 5-ht5a receptors that was comparable to that of the non-selective ligand of this receptor,lysergic acid diethylamide (lsd). although each compound had a low affinity for other receptors,5-ht5a was the only receptor for which all three compounds had a high affinity. each of the three compounds ameliorated scopolamine-induced working memory deficit in mice and improved reference memory impairment in aged rats at similar doses. further,asp5736 decreased the binding of lsd to 5-ht5a receptors in the olfactory bulb of rats in a dose-dependent manner and occupied 15%-50% of brain 5-ht5a receptors at behaviorally effective doses. these results indicate that the 5-ht5a receptor is involved in learning and memory and that treatment with 5-ht5a receptor antagonists might be broadly effective for cognitive impairment associated with not only schizophrenia but also dementia. © 2015 the authors. production and hosting by elsevier b.v. on behalf of japanese pharmacological society.