Details

Autor(en) / Beteiligte

• Cheng, Kejun
• Lee, Yong Sok
• Rothman, Richard B
• Dersch, Christina M
• Bittman, Ross W
• Jacobson, Arthur E
• Rice, Kenner C

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2011-02, Vol.54 (4), p.957-969

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2011

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 (K i = 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, K e = 0.17 and (−)-30, K e =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.