Synthesis, chiral resolution, absolute configuration assignment and pharmacological evaluation of a series of melatoninergic ligands?

MedChemComm Pub Date: 2014-05-28 DOI: 10.1039/C4MD00149D

Abstract

We report herein the racemic resolution and pharmacological evaluation of naphthalenic ligand analogues of compound 3a. Propionamide 3b and fluoroacetamide 3c showed a good pharmacological profile towards MT1, MT2 and 5-HT2C. Hence, their enantiomers were successfully separated from racemates (±)-3a and (±)-3b and evaluated for their binding affinities and antidepressant activity. Binding results revealed that (?)-R-enantiomers were more potent than (+)-S-enantiomers. Furthermore, the (?)-R-enantiomers exhibited high binding affinities with partial agonist activity at melatonin MT1 and MT2 receptor subtypes and antagonist activity at the serotonin 5-HT2C receptor subtype. The R-fluoroacetamide 3c demonstrated the most potent binding affinity towards the 5-HT2C receptor subtype (pKi = 6.73 ± 0.02).

Graphical abstract: Synthesis, chiral resolution, absolute configuration assignment and pharmacological evaluation of a series of melatoninergic ligands
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