2-[N-Acylamino(C1-C3)alkyl]indoles as MT1 Melatonin Receptor Partial Agonists, Antagonists, and Putative Inverse Agonists.

The synthesis of several novel indole melatonin analogues substituted at the 2-position with acylaminomethyl (8−11), acylaminoethyl (5a−k), or acylaminopropyl (13) side chains is reported. On the basis of a novel in vitro functional assay (specific binding of [35S]GTPγS), which can discriminate agonist from partial agonist, antagonist, and inverse agonist ligands, 5a,g,h,j and 13 were shown to be partial agonists, 5d,e and 8−11 competitive antagonists, and 5b,c,k putative inverse agonists. Binding and functional assays were performed on cloned human MT1 receptor. Structure−activity relationship considerations indicate that N-[1-aryl-2-(4-methoxy-1H-indol-2-yl)(C1−C2)alkyl]alkanamides represent a lead structure for this type of ligands.