Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia (E.J.S., H.I.A., M.K., Y.K.L., S.S.N.) and Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, NIDA and NIAAA, Bethesda, Maryland (E.W.B., D.R.C., E.S.G., A.E.J., J.A.L., K.C.R., A.S.).
Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia (E.J.S., H.I.A., M.K., Y.K.L., S.S.N.) and Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, NIDA and NIAAA, Bethesda, Maryland (E.W.B., D.R.C., E.S.G., A.E.J., J.A.L., K.C.R., A.S.)
J Pharmacol Exp Ther. 2024 Oct 18;391(2):138-151. doi: 10.1124/jpet.124.002153.
Low-efficacy mu opioid receptor (MOR) agonists may serve as novel candidate analgesics with improved safety relative to high-efficacy opioids. This study used a recently validated assay of pain-depressed behavior in mice to evaluate a novel series of MOR-selective C9-substituted phenylmorphan opioids with graded MOR efficacies. Intraperitoneal injection of dilute lactic acid (IP acid) served as a noxious stimulus to depress locomotor activity by mice in an activity chamber composed of two compartments connected by an obstructed door. Behavioral measures included (1) crosses between compartments (vertical activity over the obstruction) and (2) movement counts quantified as photobeam breaks summed across compartments (horizontal activity). Each drug was tested alone and as a pretreatment to IP acid. A charcoal-meal test and whole-body-plethysmography assessment of breathing in 5% CO were also used to assess gastrointestinal (GI) inhibition and respiratory depression, respectively. IP acid produced a concentration-dependent depression in crosses and movement that was optimally alleviated by intermediate- to low-efficacy phenylmorphans with sufficient efficacy to produce analgesia with minimal locomotor disruption. Follow-up studies with two low-efficacy phenylmorphans (JL-2-39 and DC-1-76.1) indicated that both drugs produced naltrexone-reversible antinociception with a rapid onset and a duration of ∼1 h. Potency of both drugs increased when behavior was depressed by a lower IP-acid concentration, and neither drug alleviated behavioral depression by a non-pain stimulus (IP lithium chloride). Both drugs produced weaker GI inhibition and respiratory depression than fentanyl and attenuated fentanyl-induced GI inhibition and respiratory depression. Results support further consideration of selective, low-efficacy MOR agonists as candidate analgesics. SIGNIFICANCE STATEMENT: This study used a novel set of mu opioid receptor (MOR)-selective opioids with graded MOR efficacies to examine the lower boundary of MOR efficacy sufficient to relieve pain-related behavioral depression in mice. Two novel low-efficacy opioids (JL-2-39, DC-1-76.1) produced effective antinociception with improved safety relative to higher- or lower-efficacy opioids, and results support further consideration of these and other low-efficacy opioids as candidate analgesics.
低效能μ阿片受体（MOR）激动剂可能成为新型候选镇痛药，与高效阿片类药物相比，其安全性更高。本研究使用一种最近验证的小鼠疼痛抑制行为测定法，评估一系列具有不同 MOR 效能的新型 MOR 选择性 C9-取代苯基吗啡类药物。腹腔注射稀乳酸（IP 酸）作为一种有害刺激，通过位于由阻塞门连接的两个隔室的活动室中的小鼠来抑制运动活性。行为测量包括：（1）隔室之间的交叉（穿过障碍物的垂直运动）和（2）作为光强中断总和的两个隔室之间的运动计数（水平运动）。每种药物均单独测试，并作为 IP 酸预处理进行测试。还使用炭餐试验和 5%CO 的全身 plethysmography 评估呼吸，以分别评估胃肠道（GI）抑制和呼吸抑制。IP 酸产生浓度依赖性的交叉和运动抑制，中效至低效能苯基吗啡类药物可最佳缓解，这些药物具有足够的效能产生镇痛作用，而运动活动最小。对两种低效能苯基吗啡类药物（JL-2-39 和 DC-1-76.1）的后续研究表明，两种药物均产生纳洛酮可逆转的镇痛作用，起效迅速，持续时间约 1 小时。当行为受较低 IP 酸浓度抑制时，两种药物的效力均增加，并且两种药物均不能通过非疼痛刺激（IP 氯化锂）缓解行为抑制。两种药物均产生比芬太尼弱的 GI 抑制和呼吸抑制，并且减轻了芬太尼引起的 GI 抑制和呼吸抑制。结果支持进一步考虑作为候选镇痛药的选择性、低效能 MOR 激动剂。
本研究使用一组新型具有分级 MOR 效能的μ阿片受体（MOR）选择性阿片类药物，研究了足以缓解小鼠疼痛相关行为抑制的 MOR 效能的下限。两种新型低效能阿片类药物（JL-2-39、DC-1-76.1）产生了有效的镇痛作用，与高效或低效能阿片类药物相比，安全性更高，结果支持进一步考虑这些和其他低效能阿片类药物作为候选镇痛药。
