1. Melanin-Concentrating Hormone Receptor 1 Antagonists. Synthesis and Structure–Activity Relationships of Novel 3-(Aminomethyl)quinolines
- Author
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Yuji Ishihara, Ryoma Hara, Kaneyoshi Kato, Asano Asami, Toshiro Yamashita, Shigekazu Sasaki, Shiro Takekawa, Hitomi Ogino, Nobuhiro Suzuki, Shuntaro Ashina, Yoshihide Nakano, Masahiro Kamaura, Tomoko Kaisho, Shizuo Kasai, Toshio Tanaka, Koki Kato, Shinichi Masada, Toshihiro Imaeda, Yasutaka Nagisa, and Makoto Kamata
- Subjects
Mice, Knockout ,Quinoline ,Administration, Oral ,Biological Availability ,Rats ,Melanin-concentrating hormone receptor ,Eating ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Hormone receptor ,Benzamides ,Drug Discovery ,Quinolines ,Receptor, Serotonin, 5-HT2C ,Animals ,Humans ,Molecular Medicine ,Anti-Obesity Agents ,Receptors, Somatostatin ,Serotonin Receptor 2C ,Binding affinities - Abstract
It was found that 3-(aminomethyl)quinoline derivatives showed high binding affinities for melanin-concentrating hormone receptor 1 (MCHR1) with reduced affinity for serotonin receptor 2c (5-HT2c) when the dihydronaphthalene nucleus of compound 1 (human MCHR1, IC(50) = 1.9 nM; human 5-HT2c receptor, IC(50) = 0.53 nM) was replaced by other bicyclic core scaffolds. Among the synthesized compounds, 8-methylquinoline derivative 5v especially showed high binding affinity (IC(50) = 0.54 nM), potent in vitro antagonistic activity (IC(50) = 2.8 nM) for MCHR1, and negligible affinity for 5-HT2c receptor (IC(50)1000 nM). Oral administration of 5v significantly and dose-dependently suppressed nocturnal food intake in diet-induced obese rats and did not affect food intake in MCHR1-deficient mice. These results and rat pharmacokinetic study findings suggested that compound 5v is a highly potent, orally bioavailable, and centrally acting nonpeptide MCHR1 antagonist.
- Published
- 2012