Tetrahydroquinoline Ring as a Versatile Bioisostere of Tetralin for Melatonin Receptor Ligands

A new
family of melatonin receptor ligands, characterized by a
tetrahydroquinoline (THQ) scaffold carrying an amide chain in position
3, was devised as conformationally constrained analogs of flexible N-anilinoethylamides previously developed. Molecular superposition
models allowed to identify the patterns of substitution conferring
high receptor binding affinity and to support the THQ ring as a suitable
scaffold for the preparation of melatonin ligands. The biological
activity of 3-acylamino-THQs was compared with that of the corresponding
tetralin derivatives. The THQ ring proved to be a versatile scaffold
for easy feasible MT1 and MT2 ligands, which
resulted as more polar bioisosteres of their tetralin analogs. Potent
partial agonists, with subnanomolar binding affinity for the MT2 receptor, were obtained, and a new series of THQ derivatives
is presented. The putative binding mode of potent THQs and tetralines
was discussed on the basis of their conformational equilibria as inferred
from molecular dynamics simulations and experimental NMR data.