Racemic N-(8-methoxy-10,11-dihydro-5H-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 (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.
Synthesis, Enantiomeric Resolution, and Structure-Activity Relationship Study of a Series of 10,11-Dihydro-5H-Dibenzo[a,d]cycloheptene MT(2) Receptor Antagonists / SPADONI G.; BEDINI A.; DIAMANTINI G.; TARZIA G.; RIVARA S.; LORENZI S.; LODOLA A.; MOR M.; LUCINI V.; PANNACCI M.; CARONNO A.; FRASCHINI F.. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 2(2007), pp. 1741-1749. [10.1002/cmdc.200700141]
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