title: Novel 5-HT5A receptor antagonists ameliorate scopolamine-induced working memory deficit in mice and reference memory impairment in aged rats.
abstract: 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.
authors.affiliation: Neuroscience Research Unit, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki, 305-8585, Japan. Electronic address: mayako.yamazaki@astellas.com.
authors.forename: Mayako
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Neuroscience Research Unit, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki, 305-8585, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Okabe
authors.affiliation: Neuroscience Research Unit, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki, 305-8585, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Neuroscience Research Unit, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki, 305-8585, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Yarimizu
authors.affiliation: Neuroscience Research Unit, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki, 305-8585, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Harada
mesh_terms: D000375:Aging; D000818:Animals; D001921:Brain / Q000378:metabolism; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology*; D003704:Dementia / Q000188:drug therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D008238:Lysergic Acid Diethylamide / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy*; D008815:Mice, Inbred Strains; D009830:Olfactory Bulb / Q000378:metabolism; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy; D012601:Scopolamine / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D006146:Guanidines; D007546:Isoquinolines; C000599359:N-(diaminomethylene)-1-(3,5-difluoropyridin-4-yl)-4-fluoroisoquinoline-7-carboxamide; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C078730:serotonin 5 receptor; D008238:Lysergic Acid Diethylamide; D012601:Scopolamine
keywords: 5-HT(5A) receptor; Cognitive impairment; Occupancy; Water maze; Y-maze