DISCOVERY OF SMALL-MOLECULE ORPHANIN FQ RECEPTOR LIGANDS

小分子孤啡肽 FQ 受体配体的发现

• 批准号: 7846706
• 负责人: Nurulain T Zaveri
• 金额: $ 30.44万
• 依托单位: ASTRAEA THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846706
• 关键词: 3-Dimensional; Address; Affinity; Agonist; Alcohol consumption; Alcohols; Amino Acids; Amphetamines; Analgesics; Animal Model; Anti-Anxiety Agents; Anxiety; Attenuated; Behavioral Model; Binding; Biological Availability; Blood - brain barrier anatomy; Buprenorphine; Characteristics; Chimera organism; Circadian Rhythms; Clinic; Cocaine; Complex; Cues; Development; Dimensions; Dose; Drug Addiction; Drug Design; Drug abuse; Drug usage; Family; Functional disorder; Funding; Goals; Grant; Homology Modeling; Human; Investigation; Kidney; Laboratories; Lead; Learning; Ligands; Manuscripts; Memory; Modeling; Morphine; Motivation; Mus; Names; Nociception; ORL1 receptor; Opiates; Opioid; Opioid Receptor; Pain; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Play; Positron-Emission Tomography; Preparation; Primates; Process; Psychological reinforcement; Rattus; Recovery; Regulation; Relapse; Research; Research Personnel; Rewards; Ro 64-6198; Rodent; Rodent Model; Role; Self Administration; Series; Site-Directed Mutagenesis; Stress; Structural Models; Structure; Subcutaneous Injections; Substance Addiction; Substance abuse problem; System; Therapeutic; Translations; United States National Institutes of Health; Wistar Rats; Withdrawal; Work; addiction; base; brain tissue; computer studies; craving; deprivation; design; disorder later incidence prevention; drug abuse chemotherapy; drug addiction pharmacotherapy; drug discovery; drug of abuse; drug reward; drug seeking behavior; feeding; in vivo; insight; medical schools; member; molecular recognition; new technology; next generation; nociceptin; nociceptin receptor; nonhuman primate; novel; pharmacophore; piperidine; preference; prevent; public health relevance; receptor; response; scaffold; small molecule; stimulant abuse; tool; translational study

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.

描述（由申请人提供）：痛敏素受体（NOP，以前称为阿片受体样受体ORL 1）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感受素或N/OFQ在物质滥用相关的奖赏和动机途径的调节中发挥作用。天然肽N/OFQ或唯一研究的合成激动剂Ro 64-6198的给药已显示在药物奖励和强化的各种啮齿动物模型中阻断可卡因、吗啡、安非他明和酒精的奖励作用，例如条件性位置偏好和药物自我给药。N/OFQ和Ro 64-6198还显示在焦虑的啮齿动物模型中具有抗焦虑活性，并且在应激诱导的药物寻求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，并且小分子NOP激动剂可能具有作为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，并且NOP激动剂尚未在药物自我给药和复发的转化灵长类动物模型中进行评估，这可能是因为已知的NOP激动剂要么选择性不足，要么生物利用度差。显然，需要下一代药物样化合物来生产临床上有用的药物。我们目前资助的赠款的总体目标是发现新的，选择性的和药物样的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性镇痛剂。我们已经发现了几种选择性的NOP配体，最近证明，我们的NOP激动剂SR 16835，减弱吗啡的位置偏好在小鼠和减少剥夺诱导的增加在Wistar大鼠（复发模型）饮酒。在这个竞争修订版中，为了响应通知#NOT-OD-09-058，题为：NIH宣布恢复法案资金的可用性竞争修订申请，我们建议在可卡因奖励和复发的“非人灵长类动物”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，理解导致NOP相对于其他阿片受体的选择性的受体分子识别特征是至关重要的，以便能够调节药物样特征，同时保持选择性和亲和力。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。本竞争修订版的具体目的是（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，以及（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。 公共卫生关系：NOP激动剂已显示降低与滥用药物相关的奖励效应，并且还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。本竞争修订版中针对ARRA通知NOT-OD-09-058提出的工作将通过研究我们的选择性NOP激动剂在非人灵长类动物自我给药和复发模型中的疗效，专门加速其转化。该项目还建议将目前的新技术，基于结构的药物设计，纳入我们现有的发现工作，以加速发现药物样，有效和新颖的NOP激动剂。拟议的研究将显著加快该项目的转化，以开发治疗上可行的NOP激动剂作为药物滥用治疗药物。