Synthesis, Enantiomeric Resolution, and Structure–Activity Relationship Study of a Series of 10,11‐Dihydro‐5 H ‐Dibenzo[a,d]cycloheptene MT 2 Receptor Antagonists

Racemic N ‐(8‐methoxy‐10,11‐dihydro‐5 H ‐dibenzo[a,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 (GTPγS 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 .