Increased Metabolic Stability and Reduced MOR Efficacy of a Potent C9-Substituted Phenylmorphan

Authors

• DE Hernandez
• A Sulima
• D Luo
• TE Prisinzano
• SS Negus
• N Nassehi
• DE Selley
• P Shah
• R Kato
• X Xu
• AE Jacobson
• KC Rice

Abstract

Opioid analgesics are used for chronic and acute pain management.1 However, these compounds have a variety of biological effects, most notably, their analgesic effects, with side-effects including respiratory depression, gastrointestinal effects, tolerance, and dependence.2 The abuse liability of MOR agonists, as well as their side-effects has led to the search for different and safer analgesics.3 Our recent study reported the synthesis of interesting full and partial agonists, most notably, full agonist DC-01-0076.2.4 An SAR on DC-01-0076.2 led to the discovery of compound 14, (DH-1-106; 3-((1R,5S,9R)-2-phenethyl-9-vinyl-2-azabicyclo[3.3.1]nonan-5-yl)benzamide) a potent partial agonist with an EC50 of 5.28 nM and an Emax of 75% at MOR in the cAMP accumulation assay. Most notably, we were able to increase the metabolic stability of our compound in liver microsomal assays through a bioisosteric replacement of the phenolic hydroxyl moiety. In liver microsomal assays, the half-life increased by at least 3-fold in human and mouse microsomes. In a recently validated in vivo assay of pain-depressed behavior in mice, DH-1-106 produced dose-dependent antinociception consistent with its intermediate MOR efficacy; however the duration of antinociception was shorter than for the related compound DC-01-0076.2.

Scientific Focus Area: Molecular Pharmacology

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