DISCOVERY OF SMALL-MOLECULE ORPHANIN FQ RECEPTOR LIGANDS

描述（由申请人提供）：痛觉肽受体（NOP，以前称为阿片受体样受体ORL1）是阿片受体家族的第四成员。NOP受体及其内源性配体nociceptin或orphanin FQ （N/OFQ）已被证明在与药物滥用相关的奖励和动机途径的调节中发挥作用。在各种啮齿类动物的药物奖励和强化模型中，如条件位置偏好和药物自我给药，天然肽N/OFQ或唯一研究的合成激动剂Ro 64-6198已被证明可以阻断可卡因、吗啡、安非他明和酒精的奖励作用。N/OFQ和Ro 64-6198也被证明在啮齿动物焦虑模型中具有抗焦虑活性，在啮齿动物应激诱导的药物寻求行为模型中具有抗crf活性。NOP- n /OFQ系统的抗奖励和抗应激作用的药理学特征表明，NOP受体是治疗药物滥用和复发的可行药理学靶点，小分子NOP激动剂可能具有药物滥用药物治疗的潜力。然而，治疗上可行的小分子NOP配体的开发尚未进展到临床，NOP激动剂尚未在药物自我给药和复发的翻译灵长类模型中进行评估，可能是因为已知的NOP激动剂要么没有足够的选择性，要么生物利用度差。很明显，下一代类似药物的化合物需要用于生产临床有用的药物。我们目前资助的总体目标是发现新型的、选择性的和类似药物的NOP激动剂和拮抗剂，并研究它们在阿片类和可卡因奖励的啮齿动物模型中的活性，以及它们在疼痛模型中的非成瘾性镇痛药。我们已经发现了几种选择性的NOP配体，并且最近证明了我们的NOP激动剂SR16835可以减弱小鼠的吗啡位置偏好，并减少Wistar大鼠（复发模型）中剥夺引起的饮酒增加。在此竞争性修订中，作为对题为“NIH宣布为竞争性修订申请提供恢复法案资金”的通知#NOT-OD-09-058的回应，我们建议在“非人类灵长类动物”可卡因奖励和复发模型中研究我们的NOP配体。这些研究将提供关键的信息，将加速NOP激动剂的药物滥用治疗的翻译。为了发现有用的NOP配体，了解导致NOP对其他阿片受体选择性的受体分子识别特征是至关重要的，能够在保持选择性和亲和力的同时调节药物样特征。在本修订版中，我们还建议通过将基于结构的药物设计整合到我们的药物发现工作中来增加我们的配体发现范围。这一竞争修订的具体目的是：(1)开发预测性3D-QSAR CoMFA模型和NOP受体同源性模型，以支持定点诱变研究和NOP配体设计；(2)在灵长类动物可卡因自我给药和复发模型中研究选定的NOP激动剂。

DESCRIPTION (provided by applicant): The nociceptin receptor (NOP, previously known as the opioid receptor-like receptor ORL1) is the fourth member of the opioid receptor family. The NOP receptor and its endogenous ligand nociceptin or orphanin FQ (N/OFQ) have been shown to play a role in the regulation of reward and motivation pathways related to substance abuse. Administration of the natural peptide N/OFQ or the only studied synthetic agonist Ro 64-6198 has been shown to block rewarding effects of cocaine, morphine, amphetamines and alcohol, in various rodent models of drug reward and reinforcement, such as conditioned place preference and drug self-administration. N/OFQ and Ro 64-6198 have also been shown to have anxiolytic activity in rodent models of anxiety and anti-CRF activity in rodent models of stress-induced drug-seeking behavior. This pharmacological profile of the anti-rewarding and anti-stress effects of the NOP-N/OFQ system suggest that the NOP receptor is a viable pharmacologic target for treatment of drug abuse and relapse, and that small-molecule NOP agonists may have potential as drug abuse pharmacotherapy. However, the development of therapeutically viable, small-molecule NOP ligands has not yet progressed to the clinic and NOP agonists have not yet been evaluated in translational primate models of drug self-administration and relapse, possibly, because known NOP agonists are either not sufficiently selective or have poor bioavailability. Clearly, next generation, drug-like compounds are needed to produce clinically useful medications. The overall objective of our currently funded grant is to discover novel, selective and drug-like NOP agonists and antagonists and investigate their activity in rodent models of opiate and cocaine reward and as non-addicting analgesics in models of pain. We have discovered several selective NOP ligands, and recently demonstrated that our NOP agonist SR16835, attenuates morphine place preference in mice and reduces deprivation-induced increase in alcohol drinking in Wistar rats (a model of relapse). In this Competing Revision, in response to Notice #NOT-OD-09-058, entitled: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications', we propose to study our NOP ligands in 'nonhuman primate' models of cocaine reward and relapse. These studies will provide critical information that will accelerate the translation of NOP agonists for drug abuse treatment. To discover useful NOP ligands, an understanding of the receptor molecular recognition features that lead to NOP selectivity versus other opioid receptors is critical, to be able to modulate drug-like characteristics while maintaining selectivity and affinity. In this Revision, we also propose to increase the scope of our ligand discovery by integrating structure-based drug design into our drug discovery efforts. The Specific aims of this Competing Revision are (1) develop predictive 3D-QSAR CoMFA models and a NOP receptor homology model to support the site-directed mutagenesis studies and NOP ligand design and (2) To investigate selected NOP agonists in primate models of cocaine self-administration and relapse. PUBLIC HEALTH RELEVANCE: NOP agonists have been shown to decrease the rewarding effects associated with drugs of abuse and also to have anti-stress related activity, suggesting that the NOP agonists have potential as drug abuse pharmacotherapy and for prevention of relapse. The work proposed in this Competing Revision in response to the ARRA notice NOT-OD-09-058, will specifically accelerate the translation of our selective NOP agonists by studying their efficacy in nonhuman primate models of drug self-administration and relapse. This project also proposes to incorporate current new technology, structure-based drug design, into our existing discovery efforts, to accelerate the discovery of drug-like, potent and novel NOP agonists. The proposed studies will significantly accelerate the translation of the project toward the development of therapeutically viable NOP agonists as drug abuse treatment medications.