1265913-05-0Relevant articles and documents
Probes for narcotic receptor mediated phenomena. 41. Unusual inverse μ-agonists and potent μ-opioid antagonists by modification of the N-substituent in enantiomeric 5-(3-hydroxyphenyl)morphans
Cheng, Kejun,Lee, Yong Sok,Rothman, Richard B.,Dersch, Christina M.,Bittman, Ross W.,Jacobson, Arthur E.,Rice, Kenner C.
, p. 957 - 969 (2011/04/24)
Conformational restraint in the N-substituent of enantiomeric 5-(3-hydroxyphenyl)morphans was conferred by the addition of a cyclopropane ring or a double bond. All of the possible enantiomers and isomers of the N-substituted compounds were synthesized. Opioid receptor binding assays indicated that some of them had about 20-fold higher μ-affinity than the compound with an N-phenylpropyl substituent (Ki = 2-450 nM for the examined compounds with various N-substituents). Most of the compounds acted unusually as inverse agonists in the [35S]GTP-γ-S functional binding assay using nondependent cells that stably express the cloned human μ-opioid receptor. Two of the N-substituted compounds with a cyclopropane ring were very potent μ-opioid antagonists ((+)-29, Ke = 0.17 and (-)-30, Ke =0.3) in the [35S]GTP-γ-S functional binding assay. By comparison of the geometry-optimized structures of the newly synthesized compounds, an attempt was made to rationalize their μ-opioid receptor affinity in terms of the spatial position of N-substituents. This article not subject to U.S. Copyright. Published 2011 by the American Chemical Society.
