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

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