Targeting Opioid Receptor Heterodimers for Pain Treatment

描述（由申请人提供）：大约8700万美国人和全球超过2.9亿人患有某种形式的慢性疼痛。几个世纪以来，阿片类药物一直用于治疗疼痛。然而，长期使用阿片类药物存在一些主要限制，包括：生理耐受性的发展，在所有患者中观察到的镇痛作用在长期给药期间显著降低;使人衰弱的副作用;以及药物滥用的可能性。最近来自许多实验室的证据表明，阿片受体形成寡聚体（μ阿片肽受体（MOP-R）与MOP-R相互作用并形成寡聚体复合物）和异二聚体（MOP-R与不同的阿片受体如δ阿片肽受体（DOP-R）相互作用。这些阿片样物质受体复合物产生独特的配体结合位点，与单独的受体相比具有不同的药理学特征。Gallo中心是第一个显示化合物6 '-GNTI在DOP-R和κ阿片肽受体（KOP-R）异二聚体复合物上特异性相互作用的（Waldhoer等人，2005年）。这种异源二聚体特异性配体在递送到脊髓中时引起镇痛，但在递送到脑中时不引起镇痛，因此代表了限制副作用程度和药物滥用可能性的新型治疗策略。特异性靶向阿片受体异二聚体结合位点改变了我们看待传统药理学的方式，并为药物发现提供了新的工具，可能会导致新化合物的产生。该提案的目标是开发一种药物发现平台，靶向阿片受体异二聚体复合物中的结合位点，而不是单个阿片受体。我们将使用经验证和表征的稳定阿片受体异二聚体细胞系专门开发一种靶向MOP-DOP、MOP-KOP或DOP-KOP受体异二聚体复合物的高通量钙动员试验。总体目标将是开发阿片受体异二聚体特异性药物，这些药物具有更大的组织特异性、有限的耐受性和依赖性，并改善副作用特征，减少药物滥用倾向。该提案的目标是通过开发一种药物发现平台来识别新型疼痛治疗剂，该平台靶向阿片受体异二聚体复合物中的结合位点，而不是单个阿片受体。其目的是寻找用于治疗疼痛的新型化合物，这些化合物具有增加的组织特异性，副作用和药物滥用可能性有限。

DESCRIPTION (provided by applicant): Some 87 million Americans and over 290 million individuals worldwide suffer from some form of chronic pain. For centuries opioid drugs have been used for the treatment of pain. However, there are a number of major limitations to the long-term use of opioids including: the development of physiological tolerance, a profound decrease in analgesic effect observed in all patients during prolonged administration; debilitating side-effects; and drug abuse liability potential. Recent evidence from many laboratories has shown that opioid receptors form both oligomers (the mu opioid peptide receptor (MOP-R) interacts with MOP-R and forms a oligomeric complex) and heterodimers (the MOP-R interacts with a different opioid receptor such as the delta opioid peptide receptor (DOP- R). These opioid receptor complexes produce unique ligand binding sites that have different pharmacological profiles compared to the individual receptors alone. The Gallo Center was the first to show that the compound 6'-GNTI interacts specifically at the DOP-R and kappa opioid peptide receptor (KOP-R) heterodimeric complex (Waldhoer et al., 2005). This heterodimeric specific ligand caused analgesia when delivered into the spinal cord but not when it was delivered into the brain, thus representing a novel therapeutic strategy to limit the degree of side effects and drug abuse liability potential. Specifically targeting opioid receptor heterodimeric binding sites changes the way we view traditional pharmacology and offers new tools for drug discovery that may potentially lead to the generation of novel compounds. The goal of this proposal is to develop a drug discovery platform that targets binding sites in opioid receptor heterodimeric complexes but not individual opioid receptors. We will specifically develop a high-throughput calcium mobilization assay that targets the MOP-DOP, MOP-KOP or DOP-KOP receptor heterodimer complexes using validated and characterized stable opioid receptor heterodimeric cell lines. The overall aim will be to develop opioid receptor heterodimer-specific drugs that have greater tissue specificity, limited tolerance and dependence and improved side effect profile with reduced drug abuse liability. The goal of this proposal is to identify novel pain therapeutics by developing a drug discovery platform that targets binding sites in opioid receptor heterodimeric complexes but not individual opioid receptors. The aim will be to find novel compounds for the treatment of pain that have increased tissue specificity with limited side effects and drug abuse liability potential.