Lucaj Christopher, Pitha Charlotte, Davis Jordan, Yano Hideaki
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Bouvé College of Health Sciences, Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, United States.
bioRxiv. 2025 Mar 9:2024.10.11.617959. doi: 10.1101/2024.10.11.617959.
Synthetic cannabinoid receptor agonists (SCRAs) represent a class of new psychoactive substances that pose great health risks attributed to their wide-ranging and severe adverse effects. Recent evidence has shown that SCRAs with key moieties can confer superagonism, yet this phenomenon is still not well understood. In this study, we developed a structure-activity relationship (SAR) for SCRA superagonism by comparing eight compounds differing by their head moiety (l-valinate vs. l--leucinate), core moiety (indole vs. indazole), and tail moiety (5-fluoropentyl vs. 4-fluorobenzyl) through different modes of bioluminescence resonance energy transfer (BRET). We found that l--leucinate head moiety and indazole core moiety conferred superagonism across multiple Gα proteins and β-arrestin 2. After generating CB1R mutant constructs, we found that transmembrane 2 (TM2) interactions to the head moiety of tested SCRAs at F170, F177, and H178 are key to eliciting activity. Finally, we found that l--leucinate SCRAs confer a high-efficacy response in slice electrophysiology.
合成大麻素受体激动剂（SCRAs）是一类新的精神活性物质，因其广泛且严重的不良反应而带来巨大健康风险。最近的证据表明，具有关键部分的SCRAs可产生超激动作用，但这一现象仍未得到充分理解。在本研究中，我们通过生物发光共振能量转移（BRET）的不同模式，比较了八种在头部部分（L-缬氨酸酯与L-亮氨酸酯）、核心部分（吲哚与吲唑）和尾部部分（5-氟戊基与4-氟苄基）存在差异的化合物，建立了SCRAs超激动作用的构效关系（SAR）。我们发现，L-亮氨酸酯头部部分和吲唑核心部分在多种Gα蛋白和β-抑制蛋白2上表现出超激动作用。在构建CB1R突变体后，我们发现测试的SCRAs头部部分与跨膜2（TM2）在F170、F177和H178处的相互作用是引发活性的关键。最后，我们发现L-亮氨酸酯SCRAs在脑片电生理中表现出高效应反应。
