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-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.
Spadoni
Gilberto
G
Dipartimento Farmaceutico, Università degli Studi di Parma, V.le G. P. Usberti 27A, Campus Universitario, 43100 Parma, Italy.
Bedini
Annalida
A
Diamantini
Giuseppe
G
Tarzia
Giorgio
G
Rivara
Silvia
S
Lorenzi
Simone
S
Lodola
Alessio
A
Mor
Marco
M
Lucini
Valeria
V
Pannacci
Marilou
M
Caronno
Alessia
A
Fraschini
Franco
F
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
C515697:10,11-dihydro-5H-dibenzo(a,d)cycloheptene; D003508:Cycloheptanes; D044123:Receptor, Melatonin, MT2