Pain drugs based on nicotinic receptor subtype antagonists

项目概要/摘要 慢性疼痛是一个大而昂贵的医疗问题，根据美国医学研究所的说法， 美国国家科学院，折磨着超过1亿美国人;这一比率是癌症患者人数的10倍， 冠心病患者和4倍于美国糖尿病患者的人数。疼痛的影响 每年为美国社会带来5600 - 6350亿美元的医疗保健、康复和损失成本， 工人生产力。未解决的疼痛可能导致住院时间延长，再住院率增加， 门诊就诊增加，功能下降，导致无法工作和维持 健康保险.α9α10神经元烟碱-乙酰胆碱受体（nAChRs）是一个假定的非阿片类靶点 用于治疗神经性疼痛状态。α-芋螺毒素对α9α10 nAChRs的选择性拮抗作用 由芋螺属的海洋软体动物产生的疼痛表现出急性、累积和延长的疼痛状态逆转 在神经收缩或结扎模型中。然而，这些肽类药物难以转化为实际应用。 治疗剂，只有有限数量的有目的设计的小分子α9α10拮抗剂 nAChR已在专利或科学文献中描述。我们发现了一种临床处方 这类分子是发现和开发专有高效药物的可行起点 人α9α10 nAChR的小分子拮抗剂。原型分子已经 亚微摩尔的效力。拟议的赠款目标是了解a）什么替代品 定义α9α10 nAChR的拮抗剂效力和选择性; B）这些的代谢稳定性如何 拮抗剂，和c）这些分子的什么水平是在后- 手术和神经性疼痛。拟议工作的结果将是一个主要的候选拮抗剂， 具有受体选择性、代谢稳定性和体内功效的人α9α10 nAChR。

Project Summary / Abstract Chronic pain is a large and expensive medical problem that according to the Institute of Medicine of the National Academies, afflicts greater than 100 million Americans; a rate 10X the number of cancer sufferers, 7X those with coronary heart disease and 4X the number of Americans with diabetes. The effects of pain contribute to annual costs to US society of $560-$635 billion attributable to health care, rehabilitation and lost worker productivity. Unresolved pain can result in longer hospital stays, increased rates of re-hospitalization, increased outpatient visits, and decreased ability to function which results in an inability to work and maintain health insurance. α9α10 neuronal nicotinic-acetylcholine receptors (nAChRs) are a putative non-opioid target for the treatment of neuropathic pain states. Selective antagonism of α9α10 nAChRs by α-conotoxins produced by marine mollusks of the Conus genus show acute, cumulative and extended reversal of pain states in nerve constriction or ligation models. However these peptide drugs are difficult to translate into practical therapeutics and only a limited number of purposefully-designed small molecule antagonists for α9α10 nAChRs have been described in the patent or scientific literature. We have discovered a clinically prescribed class of molecules that is a viable starting point for the discovery and development of proprietary high potency small molecule antagonists of the human α9α10 nAChRs. The prototype molecules already have submicromolar potency at the target. The proposed grant objectives are to understand a) what substitutions define antagonist potency and selectivity at α9α10 nAChRs; b) what is the metabolic stability of these antagonists and c) what levels of these molecules are required for in vivo efficacy in rodent models of post- surgical and neuropathic pain. The outcome of the proposed work will be a lead candidate antagonist of human α9α10 nAChRs with receptor selectivity, metabolic stability and in vivo efficacy.