Mixed Opioid Agonists / Cholecystokinin Antagonists for Treatment of Pain

描述(申请人提供)：最近的发现使人们对阿片类药物耐受的机制和周围神经损伤(神经性疼痛)引起的异常疼痛有了新的见解。这些状态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，这表明中枢神经系统在病理状态下具有可塑性。尤其重要的是，我有了新的见解，即“容忍”状态伴随着我异常和矛盾的阿片类药物诱导的疼痛。到目前为止，治疗慢性疼痛或防止阿片类药物耐受的发展或后果的尝试在很大程度上是基于我们对处于生理状态的神经系统的理解。毫不奇怪，阿片类药物无论是在神经性疼痛状态下还是在“耐受”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神经系统在病理状态下的特征发生了显着变化。因此，作为我们治疗尝试的目标的神经系统与我们制定的治疗策略所针对的神经系统并不相同。在这些异常疼痛状态下，一种显著的神经肽表达增强是胆囊收缩素(CCK)。事实上，CCK拮抗剂已被证明可以防止对阿片类药物的耐受性发展，甚至逆转预先建立的耐受性。具有选择性阿片激动剂/CCK拮抗剂特征的系统可用的单个小分子，将比仅有阿片激动剂具有非常显著的优势。这项提议旨在确定这种潜在的药物，并通过临床前开发来改进它们。意义：确定的候选药物是CCK拮抗剂和阿片激动剂，在神经病理性疼痛状态和阿片类药物诱导的悖论疼痛状态(即阿片耐受)中应具有巨大的活性。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而明显的优势。

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.