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

Eur J Med Chem. 2016 Nov 10:123:180-190. doi: 10.1016/j.ejmech.2016.07.029.

Youngjae Kim ¹, Hyeri Park ², Jeongeun Lee ³, Jinsung Tae ⁴, Hak Joong Kim ⁵, Sun-Joon Min ⁶, Hyewhon Rhim ⁷, Hyunah Choo ⁸

Affiliations

1 Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 02792, Republic of Korea; Department of Chemistry, College of Science, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea.
2 Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 02792, Republic of Korea.
3 Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 02792, Republic of Korea; Department of Chemistry, Korea University, Seongbuk-gu, Seoul 02841, Republic of Korea.
4 Department of Chemistry, College of Science, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea.
5 Department of Chemistry, Korea University, Seongbuk-gu, Seoul 02841, Republic of Korea.
6 Department of Applied Chemistry, Hanyang University, Gyeonggi-du, Ansan 15588, Republic of Korea.
7 Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 02792, Republic of Korea; Department of Neuroscience, Korea University of Science and Technology, Youseong-gu, Daejeon 34113, Republic of Korea.
8 Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 02792, Republic of Korea; Department of Biological Chemistry, Korea University of Science and Technology, Youseong-gu, Daejeon 34113, Republic of Korea. Electronic address: hchoo@kist.re.kr.

PMID: 27475109 DOI: 10.1016/j.ejmech.2016.07.029

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 μM) and full antagonists (IC50 = 5.57-23.1 μM) 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.

Keywords

5-HT(7) receptor; Agonist; Antagonist; Molecular docking; Serotonin.

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