期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 5, 页码 2353-2366出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm201596h
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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, IC50 = 1.9 nM; human 5-HT2c receptor, IC50 = 0.53 nM) was replaced by other bicyclic core scaffolds. Among the synthesized compounds, 8-methylquinoline derivative 5v especially showed high binding affinity (IC50 = 0.54 nM), potent in vitro antagonistic activity (IC50 = 2.8 nM) for MCHR1, and negligible affinity for 5-HT2c receptor (IC50 > 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.
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