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A Structure-Activity Relationship Study of Novel Positive Allosteric Modulators for the δ-Opioid Receptor
Owindeep Deo1, Vi Pham2, Sadia Alvi2
1Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
None:
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.
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