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

摘要

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 MT_1, MT_2 and 5-HT_(2C). 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 (-)-Renantiomers exhibited high binding affinities with partial agonist activity at melatonin MT_1 and MT_2 receptor subtypes and antagonist activity at the serotonin 5-HT_(2C) receptor subtype. The Rfluoroacetamide 3c demonstrated the most potent binding affinity towards the 5-HT_(2C) receptor subtype(pK_i = 6.73 ± 0.02).