title: Synthesis, enantiomeric resolution, and structure-activity relationship study of a series of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene MT2 receptor antagonists.
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 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.
authors: Dipartimento Farmaceutico, Università degli Studi di Parma, V.le G. P. Usberti 27A, Campus Universitario, 43100 Parma, Italy.
authors: Gilberto
authors: G
authors: Spadoni
authors: Annalida
authors: A
authors: Bedini
authors: Giuseppe
authors: G
authors: Diamantini
authors: Giorgio
authors: G
authors: Tarzia
authors: Silvia
authors: S
authors: Rivara
authors: Simone
authors: S
authors: Lorenzi
authors: Alessio
authors: A
authors: Lodola
authors: Marco
authors: M
authors: Mor
authors: Valeria
authors: V
authors: Lucini
authors: Marilou
authors: M
authors: Pannacci
authors: Alessia
authors: A
authors: Caronno
authors: Franco
authors: F
authors: Fraschini
mesh_terms: D000818:Animals; D003508:Cycloheptanes / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D041681:NIH 3T3 Cells; D021281:Quantitative Structure-Activity Relationship; D044123:Receptor, Melatonin, MT2 / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism
chemical_list: C515697:10,11-dihydro-5H-dibenzo(a,d)cycloheptene; D003508:Cycloheptanes; D044123:Receptor, Melatonin, MT2