jm5b01066_si_002.csv (1.82 kB)
Highly Potent and Selective MT2 Melatonin Receptor Full Agonists from Conformational Analysis of 1‑Benzyl-2-acylaminomethyl-tetrahydroquinolines
dataset
posted on 2015-09-24, 00:00 authored by Gilberto Spadoni, Annalida Bedini, Simone Lucarini, Michele Mari, Daniel-Henri Caignard, Jean A. Boutin, Philippe Delagrange, Valeria Lucini, Francesco Scaglione, Alessio Lodola, Franca Zanardi, Daniele Pala, Marco Mor, Silvia RivaraMolecular
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 (Ki = 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.