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

描述（由申请人提供）：NOP（孤啡肽/孤啡肽）受体是第四种阿片受体亚型，在非人灵长类动物中介导独特的作用，表明该受体的活性可能导致强烈的镇痛作用，而几乎不存在μ阿片受体（MOP）激动剂中发现的所有副作用。NOP激动剂，无论是肽类或非肽类，在我们在恒河猴中使用的三种测定中的每一种中，当局部、全身或鞘内递送时产生完全镇痛。然而，小分子NOP激动剂不充当增强剂，并且可在啮齿动物模型中产生抗增强作用。此外，我们发现MOP部分激动剂和NOP激动剂的组合在我们的猴模型中具有协同的抗伤害感受作用。这些令人兴奋的结果促使本申请评估了一种新型丁丙诺啡类似物BU 08028，该类似物是由Husbands博士开发和合成的，在恒河猴的许多试验中与MOP激动剂丁丙诺啡进行了并排比较。BU 08028对MOP和NOP受体都具有结合亲和力，并对两种受体都显示出部分激动剂作用。这些猴试验专门设计用于反映阿片类镇痛药的治疗（镇痛）和副作用（滥用倾向、生理变化和身体依赖性）特征。这些检测试剂中有许多是在本实验室开发的，并已在十年或更长时间内得到验证。在本申请的第一个目的中，将评价和比较急性和重复给药后BU 08028的作用。在第二个目标中，将通过选择性MOP和NOP拮抗剂阐明BU 08028的受体机制。在两种受体上具有激动剂作用的药物将是强效和有效的镇痛剂，副作用减少，这一可能性鼓励了我们对BU 08028的药理学研究。我们在恒河猴中的独特试验集，我们在这些动物中对这些模型的广泛研究历史，以及新型双功能MOP/NOP激动剂的可用性，为确定临床人群中疼痛和药物滥用治疗的突破奠定了基础。

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.