Bioisosteres of a Potent and Efficacious MOR Antagonist in the 5-(3-Hydroxy)phenylmorphan Series

Authors

• Z Hasanpour
• A Sulima
• L Spina
• D Luo
• TE Prisinzano
• S Pranav
• K Rintaro
• X Xu
• AE Jacobson
• KC Rice

Abstract

The prevalence of opioid use disorder (OUD) and incidence of opioid-related overdoses have increased at an alarming rate in the past decade in North America and worldwide (nearly 30% increasing from 2019 to 2020).1 The 5-(3-hydroxy)phenylmorphan molecule, as a morphine congener, has structure more simplified compared to morphine. Several potent mu opioid receptor (MOR) agonists and antagonists have been discovered in the series of C9-substituted 5-(3-hydroxy)phenylmorphans.2,3 Among them, a C9-methyl analog, 3-((1S,5R,9R)-9-methyl-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol, was of a particular interest to us. The C9-methyl analog was found to be a potent and efficacious MOR antagonist and, unlike naltrexone, was devoid of any agonist activity.4 In the current work, we have designed and synthesized several bioisosteres of the lead C9-methyl analog in the attempt to reduce metabolic instability. Structural modifications of the lead molecule will be discussed in detail along with functional activity and metabolic stability of the new bioisoesters.

Scientific Focus Area: Molecular Biology and Biochemistry

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