Deo Owindeep, Pham Vi, Alvi Sadia, Barnes Nicholas, Gondin Arisbel B, Christopoulos Arthur, Poole Daniel P, Carbone Simona E, Thal David M, Jörg Manuela, Capuano Ben, Valant Celine, Scammells Peter J
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
ACS Chem Neurosci. 2025 Aug 6;16(15):2958-2977. doi: 10.1021/acschemneuro.5c00280. Epub 2025 Jul 18.
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.
慢性疼痛和抑郁症是广泛流行的共病状况，安全有效的治疗方法有限。虽然μ-阿片受体（MOR）激动剂对治疗疼痛有效，但它们存在严重的缺点，包括依赖性、成瘾性和呼吸抑制。δ-阿片受体（DOR）因其具有减轻疼痛的潜在能力且副作用较小，提供了一种有前景的替代方案。先前的研究已经鉴定出能够通过变构作用引发偏向性的强效DOR正变构调节剂（PAMs）。我们的研究集中在围绕这些PAMs建立构效关系（SAR），研究DOR与MOR/KOR的选择性，并降低亲脂性。我们已经开发出一种新型的四唑并喹唑啉酮支架，其在G蛋白信号通路方面优于β-抑制蛋白2的募集。这种支架为设计具有特定信号特征的类药物、靶向DOR的治疗药物提供了一条有前景的途径，可能会带来慢性疼痛和抑郁症的新治疗选择，同时也为进一步的结构研究提供了一条途径。
