Toward the Definition of Stereochemical Requirements for MT2-Selective Antagonists and Partial Agonists by Studying 4-Phenyl-2-propionamidotetralin Derivatives

详细信息    查看全文

• 作者：Annalida Bedini ; Simone Lucarini ; Gilberto Spadoni ; Giorgio Tarzia ; Francesco Scaglione ; Silvana Dugnani ; Marilou Pannacci ; Valeria Lucini ; Caterina Carmi ; Daniele Pala ; Silvia Rivara ; Marco Mor
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 22, 2011
• 年：2011
• 卷：54
• 期：24
• 页码：8362-8372
• 全文大小：419K
• 年卷期：v.54,no.24(December 22, 2011)
• ISSN：1520-4804

文摘

New derivatives of 4-phenyl-2-propionamidotetralin (4-P-PDOT) were prepared and tested on cloned MT₁ and MT₂ receptors, with the purpose of merging previously reported pharmacophores for nonselective agonists and for MT₂-selective antagonists. A 8-methoxy group increases binding affinity of both (卤)-cis- and (卤)-trans-4-P-PDOT, and it can be bioisosterically replaced by a bromine. Conformational analysis of 8-methoxy-4-P-PDOT by molecular dynamics, supported by NMR data, revealed an energetically favored conformation for the (2S,4S)-cis isomer and a less favorable conformation for the (2R,4S)-trans one, fulfilling the requirements of a pharmacophore model for nonselective melatonin receptor agonists. A new superposition model, including features characteristic of MT₂-selective antagonists, suggests that MT₁/MT₂ agonists and MT₂ antagonists can share the same arrangement for their pharmacophoric elements. The model correctly predicted the eutomers of (卤)-cis- and (卤)-trans-4-P-PDOT. The model was validated by preparing three dihydronaphthalene derivatives, either able or not able to reproduce the putative active conformation of 4-P-PDOT.