Extensive Rigid Analogue Design Maps the Binding Conformation of Potent N-Benzylphenethylamine 5-HT2A Serotonin Receptor Agonist Ligands

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• 作者：Jose I. Juncosa ; Jr. ; Martin Hansen ; Lisa A. Bonner ; Juan Pablo Cueva ; Rebecca Maglathlin ; John D. McCorvy ; Danuta Marona-Lewicka ; Markus A. Lill ; David E. Nichols
• 刊名：ACS Chemical Neuroscience
• 出版年：2013
• 出版时间：January 16, 2013
• 年：2013
• 卷：4
• 期：1
• 页码：96-109
• 全文大小：556K
• 年卷期：v.4,no.1(January 16, 2013)
• ISSN：1948-7193

文摘

Based on the structure of the superpotent 5-HT_2A agonist 2-(4-bromo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine, which consists of a ring-substituted phenethylamine skeleton modified with an N-benzyl group, we designed and synthesized a small library of constrained analogues to identify the optimal arrangement of the pharmacophoric elements of the ligand. Structures consisted of diversely substituted tetrahydroisoquinolines, piperidines, and one benzazepine. Based on the structure of (S,S)-9b, which showed the highest affinity of the series, we propose an optimal binding conformation. (S,S)-9b also displayed 124-fold selectivity for the 5-HT_2A over the 5-HT_2C receptor, making it the most selective 5-HT_2A receptor agonist ligand currently known.

Keywords:

serotonin; 5-HT2A; agonist; rigid analogue; hallucinogen; molecular model