Spadoni Gilberto, Bedini Annalida, Diamantini Giuseppe, Tarzia Giorgio, Rivara Silvia, Lorenzi Simone, Lodola Alessio, Mor Marco, Lucini Valeria, Pannacci Marilou, Caronno Alessia, Fraschini Franco
Dipartimento Farmaceutico, Università degli Studi di Parma, V.le G. P. Usberti 27A, Campus Universitario, 43100 Parma, Italy.
ChemMedChem. 2007 Dec;2(12):1741-9. doi: 10.1002/cmdc.200700141.
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.
外消旋N-(8-甲氧基-10,11-二氢-5H-二苯并[a,d]环庚烯-10-基甲基)乙酰胺(化合物5)先前被鉴定为一种新型选择性褪黑素MT(2)拮抗剂，符合药效团和3D QSAR模型的要求。在本研究中，化合物5的对映体通过中压液相色谱法分离，其表现与外消旋体相同。对化合物5的酰氨基甲基侧链和C8位进行了修饰。所得类似物通常表现为褪黑素受体拮抗剂(GTPγS试验)，对MT(2)受体具有适度的选择性(高达10倍)。酰胺侧链的变化导致结合亲和力降低，而8-乙酰基衍生物12和8-甲基衍生物11分别与8-甲氧基母体化合物5具有相同的活性。用MT(2)受体模型进行的对接实验表明，其结合模式与观察到的构效关系以及化合物5对映体缺乏选择性相一致。
