5-HT7 receptor modulators: Amino groups attached to biphenyl scaffold determine functional activity

Title
5-HT7 receptor modulators: Amino groups attached to biphenyl scaffold determine functional activity
Author
민선준
Keywords
Serotonin; 5-HT7 receptor; Agonist; Antagonist; Molecular docking; HIGH-AFFINITY; SEROTONIN; BINDING; ANTAGONISTS; DERIVATIVES; SELECTIVITY; DEPRESSION; LIGANDS; PHARMACOPHORE; INHIBITORS
Issue Date
2016-11
Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Citation
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 123, Page. 180-190
Abstract
5-HT7 receptor (5-HT7R) agonists and antagonists have been reported to be used for treatment of neuropathic pain and depression, respectively. In this study, as a novel scaffold for 5-HT7R modulators, we designed and prepared a series of biphenyl-3-yl-methanamine derivatives with various amino groups. Evaluation of functional activities as well as binding affinities of the title compounds identified partial agonists (EC50 = 0.55-3.2 mu M) and full antagonists (IC50 = 5.57-23.1 mu M) depending on the amino substituents. Molecular docking study suggested that the ligand-based switch in functional activity from agonist to antagonist results from the size of the amino groups and thereby different binding modes to 5-HT7R. In particular, interaction of the ligand with Arg367 of 5-HT7R is shown to differentiate agonists and antagonists. In the pharmacophore model study, two distinct pharmacophore models can tell whether a ligand is an agonist or an antagonist. Taken together, this study provides valuable information for designing novel compounds with selective agonistic or antagonistic properties against 5-HT7R. (C) 2016 Elsevier Masson SAS. All rights reserved.
URI
https://www.sciencedirect.com/science/article/pii/S0223523416305773http://repository.hanyang.ac.kr/handle/20.500.11754/71298
ISSN
0223-5234; 1768-3254
DOI
10.1016/j.ejmech.2016.07.029
Appears in Collections:
COLLEGE OF SCIENCE AND CONVERGENCE TECHNOLOGY[E](과학기술융합대학) > CHEMICAL AND MOLECULAR ENGINEERING(화학분자공학과) > Articles
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