title: Antidepressant/anxiolytic potential and adverse effect liabilities of melanin-concentrating hormone receptor 1 antagonists in animal models.
abstract: Melanin-concentrating hormone receptor 1 (MCH1 receptor) is known to be involved in the control of mood and stress, in addition to the regulation of feeding. Here, we report further evidence that the blockade of the MCH1 receptor exhibits antidepressant and anxiolytic-like effects in a variety of animal models using TASP0382650 and TASP0489838, newly synthesized MCH1 receptor antagonists, with different scaffolds. Both TASP0382650 and TASP0489838 exhibited high affinities for human MCH1 receptor with IC50 values of 7.13 and 3.80nM, respectively. Both compounds showed potent antagonist activities at the MCH1 receptor, as assessed using MCH-increased [(35)S]GTPγS binding to human MCH1 receptor and an MCH-induced [Ca(2+)]i assay in rat MCH1 receptor expressing cells. In contrast, neither TASP0382650 nor TASP0489838 showed an affinity for the MCH2 receptor, another MCH receptor subtype. The oral administration of TASP0382650 or TASP0489838 significantly reduced the immobility time during the forced swimming test in rats, and reduced hyperemotionality induced by an olfactory bulbectomy, both of which are indicative of an antidepressant-like potential. In the olfactory bulbectomy model, the antidepressant effect of TASP0382650 appeared following a single administration, suggesting a faster onset of action, compared with current medications. Moreover, both TASP0382650 and TASP0489838 exhibited anxiolytic effects in several animal models of anxiety. In contrast, both TASP0382650 and TASP0489838 did not affect spontaneous locomotor activity, motor function, spatial memory during the Morris water maze task, or the convulsion threshold to pentylenetetrazole. These findings provide additional evidence that the blockade of the MCH1 receptor exhibits antidepressant- and anxiolytic activities with no adverse effects in experimental animal models.
authors.affiliation: Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan. Electronic address: s-chaki@so.taisho.co.jp.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Chaki
authors.affiliation: Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Shimazaki
authors.affiliation: Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Nishiguchi
authors.affiliation: Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Funakoshi
authors.affiliation: Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
authors.forename: Michihiko
authors.initials: M
authors.lastname: Iijima
authors.affiliation: Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
authors.forename: Akie
authors.initials: A
authors.lastname: Ito
authors.affiliation: Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kanuma
authors.affiliation: Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Sekiguchi
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000009:adverse effects* / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology; D000928:Antidepressive Agents / Q000009:adverse effects* / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D004644:Emotions / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D009830:Olfactory Bulb / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013550:Swimming / Q000523:psychology
chemical_list: D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D000928:Antidepressive Agents; C491208:MCHR1 protein, rat; C491209:Mchr1 protein, mouse; D017481:Receptors, Somatostatin; D016244:Guanosine 5'-O-(3-Thiotriphosphate)
keywords: Antidepressant; Anxiolytic; Melanin-concentrating hormone receptor 1 antagonist; TASP0382650; TASP0489838