Pain drugs based on nicotinic receptor subtype antagonists

项目摘要/摘要 慢性疼痛是一个巨大而昂贵的医学问题，根据美国医学研究所的说法 国家科学院，折磨着超过1亿美国人；癌症患者数量的10倍，7倍 患有冠心病的人数是美国糖尿病人数的4倍。疼痛的影响 每年给美国社会造成5600-6350亿美元的医疗保健、康复和损失成本 员工工作效率。未解决的疼痛可能会导致住院时间延长，再次住院率增加， 门诊就诊次数增加，功能能力下降，导致无法工作和维护 医疗保险。α9α10神经元型烟碱-乙酰胆碱受体(NAChRs)是一种可能的非阿片靶标 用于治疗神经病理性疼痛状态。α-芋螺毒素对α-9、α-10nAChRs的选择性拮抗 由圆锥属海洋软体动物产生的疼痛状态表现为急性、累积和延长的逆转 在神经收缩或结扎模型中。然而，这些多肽药物很难转化为实用药物。 治疗和仅有有限数量的有目的地设计的α9α10小分子拮抗剂 专利或科学文献中已经对nAChRs进行了描述。我们发现了一种临床处方 一类分子，是发现和开发专有高效性的可行起点 人α9α10nAChRs的小分子拮抗剂。原型分子已经有了 靶子的亚微摩尔效力。建议的赠款目标是了解a)哪些替代 定义α9α10nAChRs的拮抗剂效力和选择性；b)这些受体的代谢稳定性是什么 拮抗剂和c)这些分子的水平是什么水平需要在啮齿动物模型中的效果后- 外科手术和神经病理性疼痛。拟议工作的结果将是一个主要的候选对手 人α9α10nAChRs具有受体选择性、代谢稳定性和体内疗效。

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.