Kim, Youngjae Kim, Jeeyeon Tae, Jinsung Roth, Bryan L. Rhim, Hyewhon Keum, Gyochang Nam, Ghilsoo Choo, Hyunah 2024-01-20T12:30:57Z 2024-01-20T12:30:57Z 2021-09-05 2013-05-01 0968-0896 https://pubs.kist.re.kr/handle/201004/128073 It has been reported that 5-HT7 receptors are promising targets of depression and neuropathic pain. 5-HT7 receptor antagonists have exhibited antidepressant-like profiles, while agonists have represented potential therapeutics for pain. In the course of our ongoing efforts to discover novel 5-HT7 modulators, we designed an arylpiperazine scaffold with a substituted biphenyl-2-ylmethyl group. A series of biphenyl-2-yl-arylpiperazinylmethanes were then prepared, which showed a broad spectrum of binding affinities to the 5-HT7 receptor depending upon the substituents attached to the biphenyl and aryl functionalities. Among those synthesized compounds, the compounds 1-24 and 1-26 showed the best binding affinities to the 5-HT7 receptor with K-i values of 43.0 and 46.0 nM, respectively. Structure-activity relationship study in conjunction with molecular docking study proposed that the 5-HT7 receptor might have two distinctive hydrophobic binding sites, one specific for aromatic 2-OCH3 substituents within the arylpiperazine and the other for biphenyl methoxy group. (C) 2013 Elsevier Ltd. All rights reserved. English PERGAMON-ELSEVIER SCIENCE LTD RAT HYPOTHALAMUS AGONIST ANTAGONIST IDENTIFICATION DERIVATIVES SB-269970 KETONES POTENT Discovery of aryl-biphenyl-2-ylmethylpiperazines as novel scaffolds for 5-HT7 ligands and role of the aromatic substituents in binding to the target receptor Article 10.1016/j.bmc.2013.02.038 1 BIOORGANIC & MEDICINAL CHEMISTRY, v.21, no.9, pp.2568 - 2576 BIOORGANIC & MEDICINAL CHEMISTRY 21 9 2568 2576 scie scopus 000317403200015 2-s2.0-84876123672 Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic Biochemistry & Molecular Biology Pharmacology & Pharmacy Chemistry Article RAT HYPOTHALAMUS AGONIST ANTAGONIST IDENTIFICATION DERIVATIVES SB-269970 KETONES POTENT 5-HT7 receptor Agonist Antagonist Biphenyl Arylpiperazine