Mu opioid agonists with reduced side effects for the treatment of pain

描述（由申请人提供）： 需要新的方法来改善美国5000多万慢性疼痛患者的治疗选择。这项研究旨在开发一种新型阿片类镇痛药，这种镇痛药产生的耐受性较低，可能会减少阿片类药物相关的副作用。阿片配体激活G蛋白偶联受体（GPCR）以介导多种生理功能。这些受体的调节可以最终决定阿片受体配体功效的程度。缺乏GPCR调节分子组分的转基因小鼠显示出极大减弱的阿片类镇痛剂耐受性。因此，赋予非常规受体构象的阿片激动剂可以产生具有降低的耐受性的新型镇痛药。最近，Herkinorin，鼠尾草素A衍生物，被发现是一种有效的和选择性μ阿片受体（莫尔）激动剂在体外和体内。二萜的化学结构代表了一种新的领导设计阿片激动剂具有独特的药理学特性。这种选择性μ阿片受体激动剂激活受体，诱导大鼠的抗伤害感受，但在任何测试条件下都不诱导ssarrestin 2募集，也不诱导受体的内化-将其与所有已知的莫尔激动剂区分开来。本提案的最终目标是开发新型镇痛药，减少镇痛耐受性和副作用。我们将通过以下具体目标实现这一目标：1）合成衍生自Herkinorin的阿片样物质配体以去除酯酶降解位点，改善溶解度，并保持或改善莫尔选择性;和2）通过测试G蛋白信号传导的活性、功效和效力，并寻找不存在ssarrestin向莫尔的募集，以确定Herkinorin类似物的药理学性质，所述类似物有效且有力地激活莫尔。介导的G蛋白偶联。Mencuro Therapeutic Inc.是由这些化合物的发明人共同创立的，通过开发有效的μ阿片受体激动剂而没有通常的阿片副作用来商业化该技术。SARmont，LLC是一家药物发现和设计公司，由John塔利博士领导，他是西乐葆（R）和其他7种已进入市场的NCE的主要发明者。Mencuro将与SARmont签订合同，提供药物化学服务，特别是化合物合成，分子设计和结构-活性关系分析。Mencuro将进行所有体外试验。该提案的成功将导致提交II期资助，重点是进一步优化药物化学的效力和选择性，使用已建立的哺乳动物模型进行疼痛治疗的体内验证，以及IND提交所需的临床前安全性研究。 公共卫生相关性： 慢性和持续性的严重疼痛是由许多疾病引起的，每年影响超过8000万成年人。阿片类镇痛药通过靶向μ阿片受体（莫尔）阻断疼痛感知;然而，该受体也介导不希望的阿片类副作用，例如耐受性、依赖性、便秘和过量。该提案的目标是创建莫尔激动剂，其提供疼痛缓解而没有不希望的副作用。

DESCRIPTION (provided by applicant): New approaches are needed to improve the treatment options of over 50 million people in the United States suffering from chronic pain. The proposed research is designed to develop a novel class of opioid analgesics that produce less tolerance and may potentially reduce opiate-associated side effects. Opioid ligands activate G protein coupled receptors (GPCR) to mediate diverse physiological functions. The regulation of these receptors can ultimately determine the extent of opioid receptor ligand efficacy. Genetically modified mice that lack molecular components of GPCR regulation display greatly attenuated opioid analgesic tolerance. Therefore, opioid agonists conferring non-conventional receptor conformations could yield novel analgesics with reduced tolerance liabilities. Recently, Herkinorin, a salvinorin A derivative, was found to be a potent and selective mu opioid receptor (MOR) agonist in vitro and in vivo. The diterpene chemical structure represents a novel lead for the design of opiate agonists with distinct pharmacological properties. This selective mu opioid receptor agonist activates the receptor, induces antinociception in rats, yet does not induce ssarrestin2 recruitment nor induce internalization of the receptor under any condition tested - distinguishing it from all known MOR agonists. The ultimate goal of this Proposal is to develop novel analgesics with reduced analgesic tolerance and side effects. We will achieve this goal using the following Specific Aims: 1): synthesize opioid ligands derived from Herkinorin to remove esterase-degradation sites, improve solubility, and preserve or improve MOR selectivity; and 2) determine pharmacological properties of Herkinorin analogs by testing activity of G protein signaling efficacy and potency and looking for absence of ssarrestin recruitment to MOR for analogues that efficaciously and potently activate MOR-mediated G protein coupling. Mencuro Therapeutic Inc. was co-founded by the inventors of these compounds, to commercialize this technology by developing potent mu opioid receptor agonists without the usual opioid side-effects. SARmont, LLC, is a drug discovery and design company, led by Dr. John Talley, the lead inventor of Celebrex(R) and 7 other NCEs that have made it to the marketplace. Mencuro will contract SARmont to provide medicinal chemistry services, specifically in compound synthesis, molecular design, and structure- activity relationship analysis. Mencuro will conduct all the in vitro testing. Success in this Proposal will lead to the submission of a Phase II grant focused on further medicinal chemistry optimization for potency and selectivity, in vivo validation using established mammalian models for pain treatment, and pre-clinical safety studies required for IND submission. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Chronic and persistent, severe pain results from many disorders and diseases and affects over 80 million adults annually. Opioid analgesics block pain perception by targeting the mu opioid receptor (MOR); however, this receptor also mediates unwanted opioid side-effects such as tolerance, dependence, constipation and overdose. The goal of this Proposal is to create MOR agonists that provide pain relief without unwanted side-effects.