Mixed Opioid Agonists / Cholecystokinin Antagonists for Treatment of Pain

描述（由申请人提供）：最近的发现为阿片类药物耐受性和周围神经损伤引起的异常疼痛（神经性疼痛）的机制提供了新的见解。这些状态的共同特征之一是神经肽在脊髓和棘上部位的表达和活性增强，表明病理状态下中枢神经系统具有可塑性。尤其重要的是，这种“耐受”状态伴随着阿片类药物引起的异常和矛盾的疼痛。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“耐受性”状态下都不能很好地缓解疼痛。阿片类药物疗效的缺陷是由于病理状态下神经系统特征的显著改变。因此，我们尝试治疗的目标神经系统与我们开发的治疗策略并不相同。胆囊收缩素（CCK）是一种突出的神经肽，在这些异常疼痛状态下表达增强。事实上，CCK拮抗剂已被证明可以阻止耐受性的发展，甚至逆转对阿片类药物治疗的预先建立的耐受性。作为选择性阿片受体激动剂/ CCK拮抗剂，一个系统可用的单一小分子将比单独的阿片受体激动剂具有非常显著的优势。本提案旨在确定这些潜在药物并通过临床前开发来推进它们。意义：CCK拮抗剂和阿片受体激动剂候选药物的鉴定应该在神经性疼痛状态和阿片诱导的矛盾疼痛状态（即阿片耐受性）中具有巨大的活性。与现有的止痛疗法相比，这些类似药物的小分子将具有明显的优势。

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.