A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates
A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates
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DOI：
10.1073/pnas.1605295113
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发表时间：
2016-09-13
影响因子：
11.1
通讯作者：
Ko, Mei-Chuan
中科院分区：
文献类型：
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作者：
Ding, Huiping;Czoty, Paul W.;Ko, Mei-Chuan
尽管迫切需要，但以前的研究还没有证实安全的阿片类镇痛药在灵长类动物中没有滥用倾向。药物化学的最新进展已经导致开发具有混合μ阿片肽（MOP）/痛敏肽-β-FQ肽（NOP）受体激动剂活性的配体以实现该目的。BU 08028是一种新型奥维醇类似物，与丁丙诺啡具有相似的结合特征，对NOP受体的亲和力和功效有所改善。这项临床前研究的目的是使用临床使用的MOP受体激动剂在各种经过精心训练的行为和生理测定中进行并行比较，建立BU 08028在猴子中的功能特征。全身性BU 08028（0.001-0.01 mg/kg）产生有效的持久（即，> 24 h）的镇痛和抗异常性疼痛作用，可被MOP或NOP受体拮抗剂阻断。更重要的是，BU 08028的增强强度显著低于可卡因、瑞芬太尼或丁丙诺啡在猴子中的增强强度，所述猴子在药物自我给药的渐进比例时间表下响应。与MOP受体激动剂不同，通过遥测装置测量，抗伤害剂量和类似于10至30倍高剂量的BU 08028不会引起呼吸抑制或心血管不良事件。重复给药后，猴子对吗啡产生了急性身体依赖，表现为突然的戒断症状，如呼吸频率、心率和血压增加。相比之下，猴子对BU 08028没有表现出身体依赖性。这些在灵长类动物中的体内发现不仅证明了双功能MOP/NOP受体激动剂的疗效和耐受性，而且提供了将此类配体转化为安全且可能无滥用的阿片类镇痛剂的治疗方法。
Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors. The aim of this preclinical study was to establish the functional profile of BU08028 in monkeys using clinically used MOP receptor agonists for side-by-side comparisons in various well-honed behavioral and physiological assays. Systemic BU08028 (0.001-0.01 mg/kg) produced potent long-lasting (i.e., > 24 h) antinociceptive and antiallodynic effects, which were blocked by MOP or NOP receptor antagonists. More importantly, the reinforcing strength of BU08028 was significantly lower than that of cocaine, remifentanil, or buprenorphine in monkeys responding under a progressive-ratio schedule of drug self-administration. Unlike MOP receptor agonists, BU08028 at antinociceptive doses and similar to 10- to 30-fold higher doses did not cause respiratory depression or cardiovascular adverse events as measured by telemetry devices. After repeated administration, the monkeys developed acute physical dependence on morphine, as manifested by precipitated withdrawal signs, such as increased respiratory rate, heart rate, and blood pressure. In contrast, monkeys did not show physical dependence on BU08028. These in vivo findings in primates not only document the efficacy and tolerability profile of bifunctional MOP/NOP receptor agonists, but also provide a means of translating such ligands into therapies as safe and potentially abuse-free opioid analgesics.