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Eur J Med Chem. 2016 Nov 10;123:180-190. doi: 10.1016/j.ejmech.2016.07.029. Epub 2016 Jul 21.

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

Author information

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.

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

PMID:
27475109
DOI:
10.1016/j.ejmech.2016.07.029
[Indexed for MEDLINE]

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