Mixed NOP/mu compounds and the involvement of their receptors in analgesia

描述（由申请人提供）：丁丙诺啡是一种低疗效阿片类镇痛药，具有良好的副作用特征。尽管它对啮齿动物和人类都是一种强效镇痛药，但它几乎不会引起呼吸抑制，几乎不会引起戒断症状，而且持续时间很长。这些特征使得该化合物不仅适合作为镇痛剂，而且适合用于海洛因滥用药物治疗。大量证据表明，阿片受体家族的孤儿受体NOP受体（以前称为ORL 1）及其内源性配体N/OFQ（以前称为伤害感受/孤啡肽FQ）参与阿片类药物的抗伤害活性、耐受性发展和奖赏作用。最近的证据表明，丁丙诺啡的一些行为特性是由于在高浓度下与NOP受体结合。这表明，具有不同亲和力特征的其他混合NOP/mu受体化合物也可能具有抗伤害感受活性，具有低呼吸抑制和低滥用可能性。在以下应用中，将在敲除（KO）小鼠中进行实验以检验NOP受体在丁丙诺啡和SR 16435（在SRI开发的混合NOP/mu受体配体）的抗伤害感受活性中发挥不可或缺的作用的假设。在特定目的1和2中，将分别检查丁丙诺啡和SR 16435在mu、NOP和ppN/OFQ KO小鼠及其相应野生型中的抗伤害感受活性。甩尾将用于确定受体或肽参与丁丙诺啡和SR 16435在急性抗伤害感受活性中的作用。还将确定这些化合物在慢性/神经性疼痛的慢性收缩损伤（CCI）模型中的有效性。CCI手术后，将使用vonFrey细丝测定丁丙诺啡和SR 16435对各KO小鼠品系中的机械性异常性疼痛的影响，并使用甩尾试验测定热痛觉过敏的影响。Specific Aim 3将用于合成和表征新型混合NOP/mu受体配体。具有更高NOP亲和力的新丁丙诺啡类似物将在巴斯大学合成，并在体外表征结合和功能活性。将在野生型小鼠的甩尾测定中测试有前景的丁丙诺啡类似物，沿着与先前在SRI合成的NOP/mu受体化合物一起的抗伤害感受活性。还将在小鼠中使用位置条件反射程序测试强效镇痛剂的奖励性质。

DESCRIPTION (provided by applicant): Buprenorphine is a low efficacy opioid analgesic with a favorable side effect profile. Although a powerful analgesic in both rodents and humans, it causes little respiratory depression, induces few abstinence symptoms, and it is very long lasting. These characteristics have made this compound suitable not only as an analgesic, but also for heroin abuse pharmacotherapy. Considerable evidence has suggested the involvement of the orphan receptor from the opioid receptor family, NOP receptor (formerly called ORL1), and its endogenous ligand N/OFQ (formerly nociception/Orphanin FQ), in opioid actions with respect to antinociceptive activity, tolerance development, and reward. Recent evidence suggests that some of the behavioral properties of buprenorphine are due to binding to NOP receptors at high concentrations. This suggests that other mixed NOP/mu receptor compounds, with different affinity profiles, may also have antinociceptive activity with low respiratory depression and low abuse potential. In the following application, experiments will be conducted in knockout (KO) mice to test the hypothesis that NOP receptors play an integral role in the antinociceptive activity of buprenorphine and SR16435, a mixed NOP/mu receptor ligand developed at SRI. In Specific Aims 1 and 2, buprenorphine and SR16435, respectively, will be examined for antinociceptive activity in mu, NOP, and ppN/OFQ KO mice and their respective wild types. Tail flick will be used to determine the involvement of the receptors or the peptide in the actions of buprenorphine and SR16435 in acute antinociceptive activity. The effectiveness of these compounds in the Chronic Constriction Injury (CCI) model of chronic/neuropathic pain will also be determined. Following CCI surgery, the effects of buprenorphine and SR 16435 will be determined on mechanical allodynia using vonFrey filaments and thermal hyperalgesia using the tail flick assay in each of the KO mouse strains. Specific Aim 3 will be used to synthesize and characterize novel mixed NOP/mu receptor ligands. New buprenorphine analogs with higher NOP affinity will be synthesized at the University of Bath, and characterized in vitro for binding and functional activity. Promising buprenorphine analogs, along with NOP/mu receptor compounds, previously synthesized at SRI, will be tested for antinociceptive activity in the tail flick assay in wild type mice. Potent analgesics will also be tested for rewarding properties using the place conditioning procedure in mice.