Synthesis, enantiomeric resolution, and structure-activity relationship study of a series of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene MT2 receptor antagonists

Racemic N-(8-methoxy-10,11-dihydro-5H-dibenzoa,d]cyclohepten-10-ylmethyl)acetamide (compound 5) was previously identified as a novel selective MT(2) antagonist fulfilling the requirements of pharmacophore and 3D QSAR models. In this study the enantiomers of 5 were separated by medium-pressure liquid chromatography and behaved as the racemate. Compound 5 was modified at the acylaminomethyl side chain and at position C8. The resulting analogues generally behaved as melatonin receptor antagonists (GTPgammaS test) with a modest degree of selectivity (up to 10-fold) for the MT(2) receptor. Changes at the amide side chain led to a decrease in binding affinity, whereas 8-acetyl and 8-methyl derivatives 12 and 11, respectively, were as potent as the 8-methoxy parent compound 5. Docking experiments with an MT(2) receptor model suggested binding modes consistent with the observed SARs and with the lack of selectivity of the enantiomers of 5.