DISCOVERY OF SMALL-MOLECULE ORPHANIN FQ RECEPTOR LIGANDS

说明(申请人提供)：伤害素受体(NOP，以前称为阿片受体样受体ORL1)是阿片受体家族的第四个成员。NOP受体及其内源性配体伤害素或孤儿蛋白FQ(N/OFQ)已被证明在物质滥用相关的奖赏和动机通路中发挥调节作用。在各种药物奖赏和强化的啮齿动物模型中，给予天然多肽N/OFQ或唯一研究的合成激动剂Ro-6198可阻断可卡因、吗啡、苯丙胺和酒精的奖赏效应，如条件性位置偏爱和药物自我给药。N/OFQ和Ro-6198也被证明在焦虑的啮齿动物模型中具有抗焦虑活性，在应激诱导的药物寻找行为的啮齿动物模型中具有抗CRF活性。NOP-N/OFQ系统的抗奖赏和抗应激作用的药理学研究表明，NOP受体是治疗药物滥用和复发的一个可行的药理靶点，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配体的开发还没有进展到临床，NOP激动剂还没有在药物自我给药和复发的翻译灵长类动物模型中进行评估，可能是因为已知的NOP激动剂要么选择性不够，要么生物利用度较低。显然，需要下一代类药物化合物来生产临床有用的药物。我们目前资助的赠款的总体目标是发现新的、选择性的和类药物的NOP激动剂和拮抗剂，并研究它们在阿片和可卡因奖励的啮齿动物模型中的活性，以及在疼痛模型中作为非成瘾止痛剂的活性。我们已经发现了几个选择性的NOP配体，最近证明了我们的NOP激动剂SR16835可以减弱小鼠对吗啡的位置偏爱，并减少Wistar大鼠因剥夺而导致的饮酒增加(一种复发模型)。在这一竞争性修订中，为了回应#NOT-OD-09-058通知，题为：NIH宣布恢复法案资金可用于竞争性修订应用，我们建议在可卡因奖励和复发的非人类灵长类动物模型中研究我们的NOP配体。这些研究将提供关键信息，加速NOP激动剂用于药物滥用治疗的转化。为了发现有用的NOP配体，了解导致NOP相对于其他阿片受体选择性的受体分子识别特征至关重要，以便能够在保持选择性和亲和力的同时调节药物样特征。在这次修订中，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扩大我们的配体发现的范围。这一竞争性修订的具体目的是(1)开发预测性3D-QSAR CoMFA模型和NOP受体同源模型，以支持定点突变研究和NOP配体设计；(2)在可卡因自我给药和复发的灵长类动物模型中研究选定的NOP激动剂。 公共卫生相关性：NOP激动剂已被证明可减少与滥用药物相关的奖励效应，并具有抗应激相关活性，这表明NOP激动剂具有作为药物滥用药物治疗和预防复发的潜力。这项针对ARRA通知NOT-OD-09-058的竞争性修订建议的工作将通过研究我们的选择性NOP激动剂在药物自我给药和复发的非人类灵长类动物模型中的有效性来特别加速我们的选择性NOP激动剂的翻译。该项目还建议将当前的基于结构的药物设计新技术融入我们现有的发现工作中，以加速发现类药物、有效的和新型的NOP激动剂。拟议的研究将大大加快该项目向开发治疗上可行的NOP激动剂作为药物滥用治疗药物的转变。

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.