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...

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Published in:The Journal of pharmacology and experimental therapeutics 2005-05, Vol.313 (2), p.831-839
Main Authors: Chaki, Shigeyuki, Funakoshi, Takeo, Hirota-Okuno, Shiho, Nishiguchi, Mariko, Shimazaki, Toshiharu, Iijima, Michihiko, Grottick, Andrew J, Kanuma, Kosuke, Omodera, Katsunori, Sekiguchi, Yoshinori, Okuyama, Shigeru, Tran, Thuy-Anh, Semple, Graeme, Thomsen, William
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Anti-Anxiety Agents - administration & dosage
Anti-Anxiety Agents - chemistry
Antidepressive Agents - administration & dosage
Antidepressive Agents - chemistry
CHO Cells
Cricetinae
Cyclohexylamines - administration & dosage
Cyclohexylamines - chemistry
Dose-Response Relationship, Drug
Female
Humans
Male
Mice
Mice, Inbred ICR
Pregnancy
Protein Binding - drug effects
Protein Binding - physiology
Quinazolines - administration & dosage
Quinazolines - chemistry
Rats
Rats, Sprague-Dawley
Receptors, Somatostatin - antagonists & inhibitors
Receptors, Somatostatin - metabolism
Stress, Physiological - drug therapy
Stress, Physiological - metabolism
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Summary: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]GTPγS) 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.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.104.081711