Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT1/MT2) and serotoninergic 5-HT2C dual ligands (I)

As part of our ongoing interest in developing new melatoninergic ligands bearing the same pharmacological profile as agomelatine, we focused our attention on this compound as a lead. Several chemical modifications have been performed on positions C-3 and 8 of the naphthalene ring determined as primary targets for the agomelatine metabolism. Herein we report the modulation of the positions C-3 and 7 in addition of the amide side chain because of this later prominent role in the affinity profile of such ligands. Synthesized compounds were then biologically evaluated at human cloned melatoninergic and serotoninergic receptors and showed different binding affinity and intrinsic activity profiles. Compounds bearing fluoroacetamide group (compounds 4 and 5) showed a high melatoninergic binding affinity particularly towards MT1 receptor subtype. Thus, the fluoroacetamide 4 exhibited a good melatoninergic (MT1/MT2) binding affinity (70 pM) higher than the lead. Moreover, other compounds (10a, 10e, 16, 17 and 18) issued from these modulations behaved as MT1 and MT2 agonists and exhibited a sub-nanomolar binding affinity towards these receptors. However, only compounds 10e, 17 and 18 showed a sub-nanomolar binding affinity at 5-HT2C higher than the agomelatine.

A series of novel naphthalenic derivatives were synthesized. Most of the compounds showed interesting affinity and activity towards the melatoninergic receptors but only few of theme showed a sub-nanomolar binding affinity at 5-HT2C.Figure optionsDownload as PowerPoint slideHighlights
► The agomelatine is the first melatoninergic antidepressant.
► Modulation of the agomelatine structure has led to the synthesis of a series of new derivatives.
► The fluoroacetamide 4 exhibited a good melatoninergic (MT1/MT2) binding affinity (70 pM).
► Compounds 10e, 17 and 18 showed sub-nanomolar binding affinities at 5-HT2C higher than agomelatine.