Pharmacological Studies of NOP Receptors

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，表明在缺乏该受体的情况下，该受体的活性可能导致强烈的止痛 几乎所有存在于MU阿片受体(MOP)激动剂的副作用。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激动剂不起到增强剂的作用。此外，我们的初步数据表明，这些激动剂可能不会产生急性依赖或减少胃肠道转运。最后，我们发现，在我们的猴子模型中，MOP部分激动剂和NOP激动剂的组合在减少伤害性反应方面具有协同作用。这些令人兴奋的结果促使这项建议对Ziveri博士合成的新型NOP激动剂进行评估，并在恒河猴的许多测试中与MOP激动剂和目前可用的NOP激动剂进行比较。这些分析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、厌恶效应、感觉间刺激效应、胃肠转运、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。胃肠转运试验是一种新颖的方法，目前正在开发专门用于显示NOP激动剂缺乏MOP激动剂的便秘作用的可能性。在这项提案的第一个目标中，完全和部分选择性NOP激动剂 将被评估和比较。在第二个目标中，将检测在两种受体上具有高亲和力和不同效果的混合NOP/MOP激动剂。在两个受体上都有激动剂作用的药物可能是有效的、副作用减少的镇痛剂，这鼓励了我们对这些混合激动剂的评估。我们在恒河猴身上的一套独特的检测方法，我们在这些动物身上对这些模型的广泛研究历史，再加上一些令人兴奋的新型NOP相关配体的可获得性，为在临床人群中确定疼痛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 possiblity that activity at this receptor may result in strong analgesia in the absence 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. Furthermore, our preliminary data indicate that these agonists may not produce acute dependence or reduce gastrointestinal transit. Finally, we have found that combinations of MOP partial agonists and NOP agonists have a synergistic action to reduce nociceptive responses in our monkey model. These exciting results prompt this proposal to evaluate novel NOP agonists that have been synthesized by Dr. Zaveri in side-by-side comparisons with MOP agonists and the currently available NOP agonists in a number of assays in rhesus monkeys. These assays have been designed specifically to reflect the therapeutic (analgesia) and side effect (abuse liability, aversive effects, interoceptive stimulus effects, gastrointestinal transit, 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. The gastrointestinal transit assay is novel and is being developed specifically to indicate the likelihood that NOP agonists lack the constipating effects of MOP agonists. In the first aim of this proposal, full and partial selective NOP agonists will be evaluated and compared. In the second aim, mixed NOP/MOP agonists with high affinity and differing efficacies at the two receptors will be examined in the assays. The possibility that drugs with agonist actions at both receptors will be potent and effective analgesics with reduced side effects encourages our evaluation of these mixed agonists. 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 number of exciting novel NOP- related ligands, sets the stage for the identification of a breakthrough in the treatment of pain in the clinical population.