Mixed Opioid Agonists / Cholecystokinin Antagonists for Treatment of Pain

混合阿片类激动剂/胆囊收缩素拮抗剂用于治疗疼痛

• 批准号: 7690784
• 负责人: EDWARD ROBERTS
• 金额: --
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7690784
• 关键词: Acute; Affinity; Agonist; Analgesics; Animal Model; Area; Binding; Biological Assay; Biology; Cancer Patient; Cardiovascular system; Carrageenan; Cavia; Cells; Characteristics; Chemicals; Chemistry; Cholecystokinin; Cholecystokinin B Receptor; Cholecystokinin Receptor; Chromosome abnormality; Chronic; Clinic; Clinical Trials; Cytochrome P450; Data; Devazepide; Development; Disease model; Dose; Drug Interactions; Drug Kinetics; Enzymes; Equilibrium; Fentanyl; Goals; Human; Hydrolysis; In Vitro; Individual; Inflammatory; Inhibitory Concentration 50; Investigational Drugs; Lead; Legal patent; Ligation; Link; Medicine; Membrane; Metabolic; Modeling; Molecular Weight; Morphine; Mus; Narcotic Antagonists; Nervous system structure; Neuraxis; Neuropeptides; Nociception; Opiates; Opioid; Opioid Receptor; Pain; Peripheral nerve injury; Pharmaceutical Preparations; Pharmacology; Physical Dependence; Physiological; Plasma Proteins; Preparation; Primates; Principal Investigator; Process; Property; Protein Isoforms; Rattus; Relative (related person); Research; Research Personnel; Rodent; Safety; Site; Solubility; Spinal; Structure-Activity Relationship; Testing; Time; Toxicology; Treatment Protocols; Vas deferens structure; base; chronic pain; drug candidate; experience; foot; genotoxicity; ileum; in vivo; inorganic phosphate; insight; lead series; meetings; micronucleus; nerve injury; nonhuman primate; novel; painful neuropathy; pharmacophore; pre-clinical; prevent; programs; radioligand; receptor; respiratory; small molecule; species difference; treatment strategy

DESCRIPTION (provided by applicant): Recent discoveries have led to new insights into mechanisms of opioid tolerance and of abnormal pain elicited by peripheral nerve injury (neuropathic pain). One of the many common features shared by these states is enhanced expression and activity of neuropeptides at both spinal and supraspinal sites, indicative of central nervous system plasticity in pathological states. Particularly significant is the new insight that the "tolerant" state is accompanied my abnormal and paradoxical opioid-induced pain. To date, attempts to treat chronic pain or to prevent the development or consequences of opioid tolerance have been based largely on our understanding of the nervous system in the physiological state. Not surprisingly, opioids do not relieve pain well in either neuropathic pain states or in the "tolerant" state. This deficit in opioid efficacy is due to markedly altered characteristics of the nervous system in the pathological state. Thus, the nervous system which is the target of our treatment attempts is not the same as that for which our treatment strategies have been developed. One prominent neuropeptide that shows enhanced expression in these abnormal pain states is cholecystokinin (CCK). Indeed, CCK antagonists have been shown to prevent tolerance development and even reverse pre-established tolerance to opioid therapy. A single small molecule that is systemically available and has the profile of being a selective opioid agonist / CCK antagonist, would have very significant advantages over opioid agonists alone. This proposal seeks to identify such potential medicines and progress them through pre-clinical development. Significance: The identification of drug candidates which are CCK antagonists and opioid agonists should have tremendous activity in neuropathic pain states and in states of opioid-induced paradoxical pain (i.e., opioid tolerance). These small and drug-like molecules will have a clear and distinct advantage over existing pain-relieving therapies.

描述（由申请人提供）：最近的发现导致了对阿片类耐受性和外周神经损伤引起的异常疼痛（神经性疼痛）机制的新见解。这些状态共有的许多共同特征之一是脊髓和脊髓上部位神经肽的表达和活性增强，表明病理状态下中枢神经系统的可塑性。特别重要的是新的见解，即“宽容”的状态是伴随着我的异常和矛盾的阿片类药物引起的疼痛。迄今为止，治疗慢性疼痛或预防阿片类药物耐受性的发展或后果的尝试主要基于我们对生理状态下神经系统的理解。毫不奇怪，阿片类药物在神经性疼痛状态或“耐受”状态下都不能很好地缓解疼痛。阿片类药物疗效的这种缺陷是由于病理状态下神经系统的特征显著改变所致。因此，作为我们治疗尝试的目标的神经系统与我们已经开发的治疗策略的神经系统不同。在这些异常疼痛状态中表现出增强表达的一种突出的神经肽是胆囊收缩素（CCK）。事实上，CCK拮抗剂已被证明可以防止耐受性的发展，甚至逆转预先建立的阿片类药物治疗耐受性。全身可用的并且具有作为选择性阿片激动剂/ CCK拮抗剂的特征的单个小分子将比单独的阿片激动剂具有非常显著的优势。该提案旨在确定这些潜在的药物，并通过临床前开发使其取得进展。重要性：作为CCK拮抗剂和阿片激动剂的候选药物的鉴定应该在神经性疼痛状态和阿片诱导的反常疼痛状态（即，阿片耐受性）。这些小的药物样分子将比现有的止痛疗法具有明显的优势。