Design and synthesis of naphthalenic derivatives as new ligands at the melatonin binding site MT3

Naphthalenic analogs of MCA-NAT (5-methoxycarbonylamino-N-acetyltryptamine) have been synthesized and evaluated as melatonin receptor ligands. Introduction of a methoxycarbonylamino substituent at the C-7 position of the naphthalenic nucleus yields MT3 selective ligands. This selectivity can be modulated with suitable variations of the C-7 position and the acyl group on the C-1 side chain. We identified new series of compounds with affinity for the MT3 binding site in the nanomolar range, and singled out a selective ligand, (N-[2-(7-methylsulfamoyl-naphth-1-yl)ethyl]acetamide (17), with a Ki of 4.9 nM and selectivity of 1024 and 2040 versus MT1 and MT2 receptors respectively.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► MT3 is a low affinity melatoninergic binding site. ► MCA-NAT has been the first to show a good selectivity and affinity (IC50 = 2.7 nM) toward this subtype. ► Naphthalenic analogues of MCA-NAT have been synthesized and evaluated. ► Introduction of a methoxycarbonylamino substituent at the C-7 position of the naphthalenic nucleus yields MT3 selective ligands. ► Compound 17 possess a Ki of 4.9 nM and selectivity of 1024 and 2040 versus MT1 and MT2 receptors respectively.