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

描述(申请人提供)：丁丙诺啡是一种副作用较大的低效阿片类止痛药。虽然它对啮齿动物和人类都是一种强大的止痛剂，但它几乎不会引起呼吸抑制，几乎不会引起戒断症状，而且它的持续时间非常长。这些特性使该化合物不仅适合作为镇痛剂，而且还适用于海洛因滥用的药物治疗。大量证据表明，阿片受体家族中的孤儿受体NOP受体(以前称为ORL1)及其内源性配体N/OFQ(以前称为伤害性/孤儿FQ)参与了阿片类药物在抗伤害感受、耐受发展和奖赏方面的作用。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时与NOP受体结合所致。这表明，其他具有不同亲和力的NOP/MU混合受体化合物也可能具有低呼吸抑制和低滥用潜力的抗伤害活性。在接下来的应用中，将在基因敲除(KO)小鼠中进行实验，以检验NOP受体在丁丙诺啡和SR16435的抗伤害感受活性中发挥不可或缺的作用的假设，SR16435是SRI开发的NOP/u混合受体配体。在特定的目标1和2中，丁丙诺啡和SR16435将分别在MU、NOP和PPN/OFQ KO小鼠及其各自的野生型小鼠中检测抗伤害活性。甩尾将被用来确定受体或多肽参与丁丙诺啡和SR16435在急性抗伤害活性中的作用。这些化合物在慢性缩窄性损伤(CCI)慢性/神经病理性疼痛模型中的有效性也将被确定。在CCI手术后，丁丙诺啡和SR 16435将在每个KO小鼠品系中使用vonFrey细丝对机械性痛觉过敏和使用甩尾试验确定其对热痛敏的影响。特异靶3将用于合成和表征新型的NOP/MU混合受体配体。巴斯大学将合成具有更高NOP亲和力的新的丁丙诺啡类似物，并在体外表征其结合和功能活性。有希望的丁丙诺啡类似物，以及先前在SRI合成的NOP/MU受体化合物，将在野生型小鼠的甩尾试验中进行抗伤害活性测试。强效止痛药也将在小鼠身上使用Place条件反射程序进行奖励特性测试。

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.