Design and Synthesis of N-(3,3-Diphenylpropenyl)alkanamides as a Novel Class of High-Affinity MT2-Selective Melatonin Receptor Ligands

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• 作者：Annalida Bedini ; Gilberto Spadoni ; Giuseppe Gatti ; Simone Lucarini ; Giorgio Tarzia ; Silvia Rivara ; Simone Lorenzi ; Alessio Lodola ; Marco Mor ; Valeria Lucini ; Marilou Pannacci ; Francesco Scaglione
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：December 14, 2006
• 年：2006
• 卷：49
• 期：25
• 页码：7393 - 7403
• 全文大小：242K
• 年卷期：v.49,no.25(December 14, 2006)
• ISSN：1520-4804

文摘

A novel series of melatonin receptor ligands was discovered by opening the cyclic scaffolds of knownclasses of high affinity melatonin receptor antagonists, while retaining the pharmacophore elements postulatedby previously described 3D-QSAR and receptor models. Compounds belonging to the classes of 2,3- and[3,3-diphenylprop(en)yl]alkanamides and of o- or [(m-benzyl)phenyl]ethyl-alkanamides were synthesizedand tested on MT₁ and MT₂ receptors. The class of 3,3-diphenyl-propenyl-alkanamides was the mostinteresting one, with compounds having MT₂ receptor affinity similar to that of MLT, remarkable MT₂selectivity, and partial agonist or antagonist behavior. In particular, the (E)-m-methoxy cyclobutanecarboxamido derivative 18f and the di-(m-methoxy) acetamido one, 18g, have sub-nM affinity for the MT₂subtype, with more than 100-fold selectivity over MT₁, 18f being an antagonist and 18g a partial agonist onGTPS test. Docking of 18g into a previously developed MT₂ receptor model showed a binding schemeconsistent with that of other antagonists. The MT₂ expected binding affinities of the new compounds werecalculated by a previously developed 3D-QSAR CoMFA model, giving satisfactory predictions.