Anxiolytic- and antidepressant-like profile of ATC0065 and ATC0175: nonpeptidic and orally active melanin-concentrating hormone receptor 1 antagonists.
Melanin-concentrating hormone (MCH) is a cyclic peptide produced in the lateral hypothalamus. It has been implicated in a number of physiological processes including feeding behavior, energy balance, and the regulation of emotional states. Here, we report in vitro and in vivo profiles of ATC0065 [N(2)-[cis-4-({2-[4-bromo-2-(trifluoromethoxy)phenyl]ethyl}amino)cyclohexyl]-N(4), N(4)-dimethylquinazoline-2,4-diamine dihydrochloride] and ATC0175 [N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzamide hydrochloride], newly synthesized MCH receptor 1 (MCHR1) antagonists. Both ATC0065 and ATC0175 had high affinities for human MCHR1 with IC(50) values of 15.7 +/- 1.95 and 7.23 +/- 0.59 nM, respectively. Both ATC0065 (IC(50) = 21.4 +/- 1.57 nM) and ATC0175 (IC(50) = 13.5 +/- 0.78 nM) showed potent antagonist activities at MCHR1, as assessed by MCH-increased guanosine 5'-O-(3-[(35)S]thio)phosphate ([(35)S]GTPgammaS) binding to human MCHR1. Oral administration of ATC0065 (3-30 mg/kg) or ATC0175 (1-10 mg/kg) significantly reduced immobility time in the forced swimming test in rats, indicating antidepressant-like effects. Both ATC0065 and ATC0175 significantly reversed swim stress-induced anxiety in the elevated plus-maze test in rats and stress-induced hyperthermia in mice. ATC0175 significantly increased social interaction between unfamiliar rats and reduced separation-induced vocalizations in guinea pig pups, indicating anxiolytic potential. In contrast, ATC0065 and ATC0175 did not affect spontaneous locomotor activity or rotarod performance in rats. These findings indicate that ATC0065 and ATC0175 are potent and orally active MCHR1 antagonists with anxiolytic and antidepressant activity in rodents.
Chaki
Shigeyuki
S
Taisho Pharmaceutical Co., Ltd., Saitama, Japan. s.chaki@po.rd.taisho.co.jp
Funakoshi
Takeo
T
Hirota-Okuno
Shiho
S
Nishiguchi
Mariko
M
Shimazaki
Toshiharu
T
Iijima
Michihiko
M
Grottick
Andrew J
AJ
Kanuma
Kosuke
K
Omodera
Katsunori
K
Sekiguchi
Yoshinori
Y
Okuyama
Shigeru
S
Tran
Thuy-Anh
TA
Semple
Graeme
G
Thomsen
William
W
D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage* / Q000737:chemistry; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000737:chemistry; D016466:CHO Cells; D006224:Cricetinae; D003514:Cyclohexylamines / Q000008:administration & dosage* / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011247:Pregnancy; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011799:Quinazolines / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013312:Stress, Physiological / Q000188:drug therapy / Q000378:metabolism
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D003514:Cyclohexylamines; C491208:MCHR1 protein, rat; C491209:Mchr1 protein, mouse; C501653:N(2)-(4-((2-(4-bromo-2-(trifluoromethoxy)phenyl)ethyl)amino)cyclohexyl)-N(4),N(4)-dimethylquinazoline-2,4-diamine; C501654:N-(4-((4-(dimethylamino)quinazolin-2-yl)amino)cyclohexyl)-3,4-difluorobenzamide; D011799:Quinazolines; D017481:Receptors, Somatostatin