Design, Synthesis, and Biological Evaluation of 6α- and 6β-N-Heterocyclic Substituted Naltrexamine Derivatives as μ Opioid Receptor Selective Antagonists

详细信息    查看全文

• 作者：Guo Li^† ; ; Lindsey C. Aschenbach^† ; ; Jianyang Chen^† ; ^§ ; ; Michael P. Cassidy^‡ ; ; David L. Stevens^‡ ; ; Bichoy H.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：March 12, 2009
• 年：2009
• 卷：52
• 期：5
• 页码：1416-1427
• 全文大小：493K
• 年卷期：v.52,no.5(March 12, 2009)
• ISSN：1520-4804

文摘

Opioid receptor selective antagonists are important pharmacological probes in opioid receptor structural characterization and opioid agonist functional study. Thus far, a nonpeptidyl, highly selective and reversible μ opioid receptor (MOR) antagonist is unavailable. On the basis of our modeling studies, a series of novel naltrexamine derivatives have been designed and synthesized. Among them, two compounds were identified as leads based on the results of in vitro and in vivo assays. Both of them displayed high binding affinity for the MOR (K_i = 0.37 and 0.55 nM). Compound 6 (NAP) showed over 700-fold selectivity for the MOR over the δ receptor (DOR) and more than 150-fold selectivity over the κ receptor (KOR). Compound 9 (NAQ) showed over 200-fold selectivity for the MOR over the DOR and approximately 50-fold selectivity over the KOR. Thus these two novel ligands will serve as leads to further develop more potent and selective antagonists for the MOR.