5-HT7receptor (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.
Bibliographical noteFunding Information:
This research was supported by the Basic Science Research Program ( NRF-2013-R1A1A2A10009907 ) and the Original Technology Research Program ( NRF-2016M3C7A1904344 ) funded by the National Research Foundation of Korea . Additional funding was provided by the Korea Institute of Science and Technology (KIST) Institutional Program ( 2E26650 and 2E26663 ). Binding affinity data were generously provided by the US National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (contract: HHSN-271-2008-00025-C ).
© 2016 Elsevier Masson SAS
All Science Journal Classification (ASJC) codes
- Drug Discovery
- Organic Chemistry