Highly Potent and Selective MT2 Melatonin Receptor Full Agonists from Conformational Analysis of 1-Benzyl-2-acylaminomethyl-tetrahydroquinolines

Journal of Medicinal Chemistry
Gilberto SpadoniS Rivara

Abstract

Molecular superposition models guided the design of novel melatonin receptor ligands characterized by a 2-acylaminomethyltetrahydroquinoline scaffold. Starting from the structure of N-anilinoethylamide ligands, the flexible chain was conformationally constrained to reproduce the bioactive conformation of melatonin. Structure-activity relationships were investigated, focusing on the substituent at the nitrogen atom, the position of the methoxy group, and the replacement of the amide side chain by urea and thiourea groups. The compounds were tested for binding affinity and intrinsic activity at human MT1 and MT2 receptors. Structural optimization resulted in N-[(1-benzyl-1,2,3,4-tetrahydro-5-methoxyquinolin-2-yl)methyl]propionamide (UCM1014), with picomolar MT2 binding affinity (K(i) = 0.001 nM), more than 10000-fold selectivity over the MT1 receptor, and a full agonist profile (GTPγS test), being the most potent MT2-selective full agonist reported to date. Molecular dynamics simulations provided a rationale for high binding affinity, stereoselectivity, and agonist behavior of these novel melatonin receptor ligands based on superposition models and conformational preference.

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Citations

Apr 16, 2016·Expert Opinion on Therapeutic Targets·Paul Pévet
Jun 18, 2016·British Journal of Pharmacology·Ralf JockersDarius P Zlotos
Jul 15, 2017·British Journal of Pharmacology·Erika CeconRalf Jockers
Apr 3, 2019·Journal of Pineal Research·Paul KlosenMarie Paule Felder-Schmittbuhl
Aug 24, 2019·Journal of Pineal Research·Erika CeconRalf Jockers
May 23, 2020·Organic & Biomolecular Chemistry·Xiaoyu YangShuai-Shuai Li
Dec 23, 2017·Expert Opinion on Drug Discovery·Hanan Awad AlkoziJesus Pintor
Jun 13, 2020·Journal of Pineal Research·Jean A BoutinDarius P Zlotos
Feb 19, 2021·Chemical Reviews·Jiarong ShiYang Li
Apr 10, 2019·Chemical Reviews·Isravel MuthukrishnanJ Carlos Menéndez
Mar 30, 2018·Journal of Medicinal Chemistry·Silvia RivaraGilberto Spadoni

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