Effects of a Buprenorphine Analog with Mixed MOP/NOP Actions in Primates

描述(申请人提供)：NOP(Nociceptin/Orphanin FQ多肽)受体，第四种阿片受体亚型，在非人类灵长类动物中介导独特的作用，这表明该受体的活性可能导致强烈的止痛，几乎没有MU阿片受体(MOP)激动剂中发现的所有副作用。NOP激动剂，无论是多肽的还是非多肽的，在我们在恒河猴身上使用的三种方法中的每一种中，当局部、全身或鞘内给药时，都会产生完全的镇痛。然而，小分子NOP激动剂不能作为增强剂，可能会在啮齿动物模型中产生抗强化作用。此外，我们发现在我们的猴子模型中，MOP部分激动剂和NOP激动剂的组合具有协同的抗伤害效应。这些令人兴奋的结果促使该应用程序对一种新的丁丙诺啡类似物BU08028进行评估，该类似物是由赫本斯博士开发和合成的，在恒河猴的多项测试中与MOP激动剂丁丙诺啡进行了并列比较。BU08028在MOP和NOP受体上都有结合亲和力，并在这两种受体上表现出部分激动剂作用。这些猴子试验是专门为反映阿片类镇痛剂的治疗(止痛)和副作用(滥用倾向、生理变化和身体依赖)而设计的。这些分析中的许多都是在这个实验室开发的，并在十年或更长的时间里得到了验证。在本应用的第一个目的中，将评估和比较BU08028在急性和重复给药后的效果。第二个目的是通过选择性的MOP和NOP拮抗剂来阐明BU08028的受体机制。在两个受体上都有激动剂作用的药物可能是有效的镇痛剂，副作用减少，这鼓励了我们对BU08028的药理学研究。我们在恒河猴身上的一套独特的分析方法，我们在这些动物中对这些模型的广泛研究历史，再加上一种新型的双功能MOP/NOP激动剂的可用性，为在临床人群中确定疼痛和药物滥用治疗方面的突破奠定了基础。

DESCRIPTION (provided by applicant): The NOP (Nociceptin/Orphanin FQ peptide) receptor, the fourth opioid receptor subtype, mediates distinctive actions in non-human primates that suggest the possibility that activity at this receptor may result in strong analgesia in the absenc of virtually all of the side effects that are found in mu opioid receptor (MOP) agonists. NOP agonists, either peptidic or non-peptidic, produce full analgesia in each of the three assays that we use in rhesus monkeys, when delivered locally, systemically, or intrathecally. Yet small molecule NOP agonists do not serve as reinforcers and may produce anti- reinforcing effects in rodent models. Furthermore, we have found that combinations of MOP partial agonists and NOP agonists have synergistic antinociceptive effects in our monkey models. These exciting results prompt this application to evaluate a novel buprenorphine analog, BU08028, that has been developed and synthesized by Dr. Husbands in side-by-side comparisons with the MOP agonist, buprenorphine, in a number of assays in rhesus monkeys. BU08028 has binding affinities on both MOP and NOP receptors and displays partial agonist actions on both receptors. These monkey assays have been designed specifically to reflect the therapeutic (analgesia) and side effect (abuse liability, physiological changes and physical dependence) profile of opioid analgesics. Many of these assays were developed in this laboratory and have been validated over the course of a decade or more. In the first aim of this application, effects o BU08028 following acute and repeated administration will be evaluated and compared. In the second aim, the receptor mechanisms of BU08028 will be elucidated by selective MOP and NOP antagonists. The possibility that drugs with agonist actions at both receptors will be potent and effective analgesics with reduced side effects encourages our pharmacological studies of BU08028. Our unique set of assays in rhesus monkeys, our extensive history of research on these models in these animals, in combination with the availability of a novel bifunctional MOP/NOP agonist, sets the stage for the identification of a breakthrough in the treatment of pain and drug abuse in the clinical population.