Design and Synthesis ofN-(3,3-Diphenylpropenyl)alkanamides as a Novel Class of High-Affinity MT₂-Selective Melatonin Receptor Ligands

A novel series of melatonin receptor ligands was discovered by opening the cyclic scaffolds of known classes of high affinity melatonin receptor antagonists, while retaining the pharmacophore elements postulated by previously described 3D-QSAR and receptor models. Compounds belonging to the classes of 2,3- and [3,3-diphenylprop(en)yl] alkanamides and of o- or [(m-benzyl) phenyl] ethyl-alkanamides were synthesized and tested on MT1 and MT2 receptors. The class of 3,3-diphenyl-propenyl-alkanamides was the most interesting one, with compounds having MT2 receptor affinity similar to that of MLT, remarkable MT2 selectivity, and partial agonist or antagonist behavior. In particular, the (E)-m-methoxy cyclobutanecarboxamido derivative 18f and the di-(m-methoxy) acetamido one, 18g, have sub-nM affinity for the MT2 subtype, with more than 100-fold selectivity over MT1, 18f being an antagonist and 18g a partial agonist on GTP gamma S test. Docking of 18g into a previously developed MT2 receptor model showed a binding scheme consistent with that of other antagonists. The MT2 expected binding affinities of the new compounds were calculated by a previously developed 3D-QSAR CoMFA model, giving satisfactory predictions.