A Structure-Activity Relationship Study of Novel Positive Allosteric Modulators for the δ-Opioid Receptor

  • ACS Chem Neurosci. 2025 Aug 6;16(15):2958-2977. doi: 10.1021/acschemneuro.5c00280.
Owindeep Deo  1 ,  Vi Pham  2 ,  Sadia Alvi  2 ,  Nicholas Barnes  2 ,  Arisbel B Gondin  2 ,  Arthur Christopoulos  2  3  4 ,  Daniel P Poole  2 ,  Simona E Carbone  2 ,  David M Thal  2  3 ,  Manuela Jörg  1 ,  Ben Capuano  1 ,  Celine Valant  2  3 ,  Peter J Scammells  1
Affiliations
  • 1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • 2. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • 3. Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
  • 4. Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
PMID: 40679069 DOI: 10.1021/acschemneuro.5c00280
Abstract

Chronic pain and depression are widely prevalent comorbid conditions with limited safe, yet effective treatments. While μ-opioid receptor (MOR) agonists are effective for treating pain, they are plagued with significant drawbacks, including dependence, addiction, and respiratory depression. The δ-opioid receptor (DOR) offers a promising alternative due to its potential ability to reduce pain but with a reduced side effect profile. Previous studies have identified potent DOR positive allosteric modulators (PAMs) capable of eliciting bias through allostery. Our research has focused on developing the structure-activity relationship (SAR) around these PAMs, investigating DOR vs MOR/KOR selectivity, and lowering lipophilicity. We have developed a novel tetrazoloquinazolinone scaffold, which exhibits G protein-pathway favorability over β-arrestin2 recruitment. This scaffold offers a promising avenue for designing drug-like, DOR-targeted therapeutics with specific signaling profiles, potentially leading to new treatment options for chronic pain and depression, as well as providing an avenue for utilization in further structural studies.

Keywords
allosteric modulator; biased modulation; chronic pain; operational model of allosterism; structure−activity relationship; δ-opioid receptor.
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