Obeng Samuel, Urquhart Kyle R, Fukuda Saki, Pallares Victoria L C, McMahon Lance R, Fantegrossi William E, Hiranita Takato
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA.
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
Neuropharmacology. 2025 Nov 15;279:110603. doi: 10.1016/j.neuropharm.2025.110603. Epub 2025 Jul 26.
Opioid overdose is the leading cause of unintentional drug-related deaths in the United States (US), largely due to the use of illicitly manufactured synthetic opioids like fentanyl and its analogs. The pharmacological properties of novel fentanyl analogs are largely unknown. Thus, this study characterized opioid-like activities of six novel fentanyl analogs (acryl fentanyl, β-hydroxythio fentanyl, cyclohexyl fentanyl, 4-fluoroisobutyrly fentanyl, furanyl fentanyl, and tetrahydrofuranyl fentanyl) in vitro and in vivo, in comparison to morphine and fentanyl. In radioligand binding assays using [H](D-Ala, N-MePhe, Gly-ol)-enkephalin (DAMGO) and the human mu opioid receptor (MOR) stably expressed in Chinese hamster ovary cells, all test substances except cyclohexyl fentanyl exhibited sub-nanomolar affinity for MOR. Furthermore, assessments of stimulation of [S]guanosine 5'-O-[γ-thio]triphosphate (GTPγS) binding at the MOR indicated that all test substances functioned as MOR agonists (E in % of DAMGO: 69.8-105), except for cyclohexyl fentanyl (13.3 %). In the warm water tail withdrawal procedure (55 °C) using male CD1 mice, cumulative injections of each test substance (S.C., N = 8 per group) produced dose-dependent increases in tail-flick latency (EDs: 0.158-3.18 mg/kg), which were blocked by the opioid receptor antagonist naltrexone. The antinociceptive potencies of each test substance were similar to or less than that of fentanyl (ED: 0.122 mg/kg). Additional in vivo studies using morphine discrimination, locomotor activity, and assessments of precipitated withdrawal further corroborated the MOR effects of these fentanyl analogs. Importantly, all the analogs produced morphine-like subjective effects suggesting that these compounds may have abuse liabilities similar to morphine.
阿片类药物过量是美国与药物相关的意外死亡的主要原因，这主要归因于非法制造的合成阿片类药物的使用，如芬太尼及其类似物。新型芬太尼类似物的药理学特性在很大程度上尚不清楚。因此，本研究对六种新型芬太尼类似物（丙烯酰芬太尼、β-羟基硫代芬太尼、环己基芬太尼、4-氟异丁酰芬太尼、呋喃基芬太尼和四氢呋喃基芬太尼）在体外和体内的阿片样活性进行了表征，并与吗啡和芬太尼进行了比较。在使用H-脑啡肽（DAMGO）和稳定表达于中国仓鼠卵巢细胞中的人μ阿片受体（MOR）的放射性配体结合试验中，除环己基芬太尼外，所有受试物质对MOR均表现出亚纳摩尔亲和力。此外，对MOR处[S]鸟苷5'-O-[γ-硫代]三磷酸（GTPγS）结合刺激的评估表明，除环己基芬太尼（13.3%）外，所有受试物质均作为MOR激动剂发挥作用（以DAMGO的百分比表示的效能：69.8-105）。在使用雄性CD1小鼠的温水甩尾程序（55°C）中，每组皮下注射每种受试物质（每组N=8）的累积注射导致甩尾潜伏期呈剂量依赖性增加（ED50：0.158-3.18mg/kg），这被阿片受体拮抗剂纳曲酮阻断。每种受试物质的镇痛效力与芬太尼相似或低于芬太尼（ED50：0.122mg/kg）。使用吗啡辨别、运动活性和戒断诱发评估的其他体内研究进一步证实了这些芬太尼类似物对MOR的作用。重要的是，所有类似物都产生了吗啡样的主观效应，表明这些化合物可能具有与吗啡相似的滥用倾向。
