Departments of Pharmacology (D.R.M., L.R.G., C.P.F.) and Psychiatry (C.P.F.), and Addiction Research, Treatment & Training Center of Excellence (D.R.M., L.R.G., C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas; Department of Pharmacy and Pharmacology (G.C.-K., S.M.H.) and Centre for Therapeutic Innovation (S.M.H.), University of Bath, Bath, United Kingdom; and Orexigen Therapeutics, La Jolla, California (B.B., P.F.).
Departments of Pharmacology (D.R.M., L.R.G., C.P.F.) and Psychiatry (C.P.F.), and Addiction Research, Treatment & Training Center of Excellence (D.R.M., L.R.G., C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas; Department of Pharmacy and Pharmacology (G.C.-K., S.M.H.) and Centre for Therapeutic Innovation (S.M.H.), University of Bath, Bath, United Kingdom; and Orexigen Therapeutics, La Jolla, California (B.B., P.F.)
J Pharmacol Exp Ther. 2020 Feb;372(2):205-215. doi: 10.1124/jpet.119.261511. Epub 2019 Nov 20.
There is an urgent need for new pharmacological treatments for substance use disorders, including opioid use disorder, particularly for use in relapse prevention. A combination of buprenorphine with naltrexone has shown particular promise, with clinical studies indicating a substantial improvement over treatment with naltrexone alone. OREX-1019 (formerly BU10119) is a compound that mimics the pharmacology of the buprenorphine/naltrexone combination. This study evaluated, in rhesus monkeys, the therapeutic potential of OREX-1019 for treating opioid use disorder. Pretreatment with OREX-1019 (0.01-0.3 mg/kg s.c.) dose-dependently decreased responding for the opioid receptor agonist remifentanil in rhesus monkeys but did not maintain levels of responding above vehicle when it was available for self-administration. OREX-1019 (0.01-1.0 mg/kg s.c.) also decreased cue- plus heroin-primed reinstatement of extinguished responding in monkeys that self-administered remifentanil but did not alter cue- plus cocaine-primed reinstatement of responding in monkeys that self-administered cocaine. OREX-1019 (0.3 mg/kg s.c.), like naltrexone (0.1 mg/kg s.c.), increased heart rate and blood pressure, produced overt observable signs, and eliminated food-maintained responding in monkeys treated chronically with morphine. These results confirm that OREX-1019 has little or no efficacy at opioid receptorsand has low abuse potential, and, combined with promising safety (clean profile vs. other off-target proteins including the hERG (human -related gene) K channel) and pharmacokinetic data (supporting administration by subcutaneous or sublingual routes, but with low oral bioavailability), suggest it could be a safe and effective alternative to current treatments for opioid use disorders particularly as applied to relapse prevention. SIGNIFICANCE STATEMENT: The novel opioid OREX-1019 potentially provides an improved relapse prevention agent for use in opioid use disorder. The current study demonstrates that in monkeys OREX-1019 is able to inhibit the self-administration of, and cue- plus heroin-primed reinstatement of, responding previously maintained by remifentanil.
目前非常需要新的药物疗法来治疗物质使用障碍，包括阿片类药物使用障碍，尤其是用于预防复发。丁丙诺啡与纳曲酮联合使用具有特殊的前景，临床研究表明，与单独使用纳曲酮相比，这种联合使用有了实质性的改善。OREX-1019（以前称为 BU10119）是一种模拟丁丙诺啡/纳曲酮联合用药药理学的化合物。本研究评估了 OREX-1019 在恒河猴中治疗阿片类药物使用障碍的潜力。在恒河猴中，预先给予 OREX-1019（0.01-0.3mg/kg 皮下注射）剂量依赖性地降低了对阿片类受体激动剂瑞芬太尼的反应，但当它可用于自我给药时，并未将反应水平维持在载体之上。OREX-1019（0.01-1.0mg/kg 皮下注射）还降低了在恒河猴中自我给予瑞芬太尼的情况下，线索加海洛因引发的已消退反应的复燃，但并未改变在恒河猴中自我给予可卡因的情况下，线索加可卡因引发的反应的复燃。与纳曲酮（0.1mg/kg 皮下注射）一样，OREX-1019（0.3mg/kg 皮下注射）增加了心率和血压，产生了明显的可观察到的体征，并消除了长期接受吗啡治疗的猴子的食物维持反应。这些结果证实，OREX-1019 对阿片受体几乎没有或没有疗效，滥用潜力低，并且结合有前途的安全性（与其他非靶点蛋白（包括 hERG（人类相关基因）K 通道）相比干净的特征）和药代动力学数据（支持通过皮下或舌下途径给药，但口服生物利用度低），表明它可能是一种安全有效的阿片类药物使用障碍治疗的替代药物，特别是在预防复发方面。意义声明：新型阿片类药物 OREX-1019 可能为阿片类药物使用障碍提供一种改进的预防复发药物。本研究表明，在恒河猴中，OREX-1019 能够抑制先前由瑞芬太尼维持的自我给药以及线索加海洛因引发的复燃。
