Pharmacological Studies of NOP Receptors

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在缺乏阿片受体时的强烈镇痛作用。 μ阿片受体（MOP）激动剂中发现的几乎所有副作用。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激动剂不作为抑制剂。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性或减少胃肠道传输。最后，我们发现MOP部分激动剂和NOP激动剂的组合具有协同作用，以减少我们的猴模型中的伤害性反应。这些令人兴奋的结果促使该建议评估Zaveri博士在与MOP激动剂和目前可用的NOP激动剂在恒河猴中的许多测定中进行并排比较中合成的新型NOP激动剂。这些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、厌恶效应、内感受性刺激效应、胃肠道转运、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。胃肠道转运试验是新的，正在专门开发，以表明NOP激动剂缺乏MOP激动剂的便秘作用的可能性。在该建议的第一个目的中，完全和部分选择性NOP激动剂 将进行评估和比较。在第二个目的中，将在测定中检查对两种受体具有高亲和力和不同功效的混合NOP/MOP激动剂。在两种受体上都具有激动剂作用的药物将是强效且有效的镇痛剂且副作用减少的可能性鼓励我们对这些混合激动剂进行评估。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，以及许多令人兴奋的新型NOP相关配体的可用性，为临床人群中疼痛治疗的突破性鉴定奠定了基础。 公共卫生相关性：拟议的研究与公共卫生有关，因为它可能导致确定无滥用和无便秘的强效镇痛药，其作用是通过第四种阿片受体亚型，NOP受体介导的。鉴定具有较少副作用的上级镇痛剂长期以来一直是疼痛管理的目标，并且此类药物可以深刻地影响人类痛苦以及降低由目前可用的强效阿片类镇痛剂造成的药物滥用风险。

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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it could result in the identification of abuse-free and constipation-free strong analgesics whose effects are mediated through the fourth opioid receptor subtype, the NOP receptor. Identification of a superior analgesic with fewer side effects has long been a goal of pain management, and such drugs could profoundly impact human suffering as well as reducing the risks of drug abuse that are posed by the currently available strong opioid analgesics.