Synthesis, enantiomeric resolution, and structure-activity relationship study of a series of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene MT2 receptor antagonists
Articolo
Data di Pubblicazione:
2007
Citazione:
Synthesis, enantiomeric resolution, and structure-activity relationship study of a series of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene MT2 receptor antagonists / G. Spadoni, A. Bedini, G. Diamantini, G. Tarzia, S. Rivara, S. Lorenzi, A. Lodola, M. Mor, V. Lucini, M. Pannacci, A. Caronno, F. Fraschini. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 2:12(2007 Dec), pp. 1741-1749. [10.1002/cmdc.200700141]
Abstract:
Racemic N-(8-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ylmethyl)acetamide (compound 5)was previously identified as a novel selective MT2 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 (GTPgS test)with a modest degree of selectivity (up to 10-fold)for the MT2 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 MT2 receptor model suggested binding modes consistent with the
observed SARs and with the lack of selectivity of the enantiomers of 5.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Docking; Medicinal chemistry; Melatonin; MT2 antagonists; Structure-activity relationships
Elenco autori:
G. Spadoni, A. Bedini, G. Diamantini, G. Tarzia, S. Rivara, S. Lorenzi, A. Lodola, M. Mor, V. Lucini, M. Pannacci, A. Caronno, F. Fraschini
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