title: ASP5736, a novel 5-HT5A receptor antagonist, ameliorates positive symptoms and cognitive impairment in animal models of schizophrenia.
abstract: We recently identified ASP5736, (N-(diaminomethylene)-1-(3,5-difluoropyridin-4-yl)-4-fluoroisoquinoline-7-carboxamide (2E)-but-2-enedioate), a novel antagonist of 5-HT5A receptor, and here describe the in vitro and in vivo characterization of this compound. ASP5736 exhibited a high affinity for the human 5-HT5A receptor (Ki = 3.6 ± 0.66 nM) and antagonized 5-carboxamidotryptamine (5-CT)-induced Ca(2+) influx in human cells stably expressing the 5-HT5A receptor with approximately 200-fold selectivity over other receptors, including other 5-HT receptor subtypes, enzymes, and channels except human 5-HT2c receptor (Ki = 286.8 nM) and 5-HT7 receptor (Ki = 122.9 nM). Further, ASP5736 dose-dependently antagonized the 5-CT-induced decrease in cAMP levels in HEK293 cells stably expressing the 5-HT5A receptor. We then evaluated the effects of ASP5736 on cognitive impairments in several animal models of schizophrenia. Working memory deficit in MK-801-treated mice and visual learning deficit in neonatally phencyclidine (PCP)-treated mice were both ameliorated by ASP5736. In addition, ASP5736 also attenuated MK-801- and methamphetamine (MAP)-induced hyperactivity in mice without causing sedation, catalepsy, or plasma prolactin increase. The addition of olanzapine did not affect ASP5736-induced cognitive enhancement, and neither the sedative nor cataleptogenic effects of olanzapine were worsened by ASP5736. These results collectively suggest that ASP5736 is a novel and potent 5-HT5A receptor antagonist that not only ameliorates positive-like symptoms but also cognitive impairments in animal models of schizophrenia, without adverse effects. Present studies also indicate that ASP5736 holds potential to satisfy currently unmet medical needs for the treatment of schizophrenia by either mono-therapy or co-administered with commercially available antipsychotics.
authors.affiliation: Department of Neuroscience, Pharmacology Research Laboratory, 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: Department of Neuroscience, Pharmacology Research Laboratory, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Harada
authors.affiliation: Department of Neuroscience, Pharmacology Research Laboratory, 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: Department of Neuroscience, Pharmacology Research Laboratory, 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: Department of Neuroscience, Pharmacology Research Laboratory, 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: Department of Neuroscience, Pharmacology Research Laboratory, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimada
authors.affiliation: Department of Neuroscience, Pharmacology Research Laboratory, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Keni
authors.initials: K
authors.lastname: Ni
authors.affiliation: Department of Neuroscience, Pharmacology Research Laboratory, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Matsuoka
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002375:Catalepsy / Q000188:drug therapy / Q000503:physiopathology; D003072:Cognition Disorders / Q000188:drug therapy / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000503:physiopathology; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology; D012702:Serotonin Antagonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D006146:Guanidines; D007546:Isoquinolines; C000599359:N-(diaminomethylene)-1-(3,5-difluoropyridin-4-yl)-4-fluoroisoquinoline-7-carboxamide; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C078730:serotonin 5 receptor; C104425:serotonin 7 receptor; D000242:Cyclic AMP; D002118:Calcium
keywords: 5-HT(5A) receptor antagonist; Adverse effect; Co-administration; Cognitive impairment; Schizophrenia