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

Mu 阿片受体激动剂可减少治疗疼痛的副作用

• 批准号: 8199288
• 负责人: Chad E. Groer
• 金额: $ 26.42万
• 依托单位: MENCURO THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8199288
• 关键词: Absence of pain sensation; Adult; Adverse effects; Affect; Agonist; Analgesics; Animal Model; Attenuated; Biological Assay; Cells; Chemical Structure; Chemicals; Chronic; Constipation; Contracts; Coupling; Dependence; Disease; Diterpenes; Drug Design; Drug Kinetics; Esthesia; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Grant; In Vitro; Individual; Lead; Ligands; Marketing; Mediating; Modeling; Molecular; Molecular Conformation; Mus; Opiates; Opioid; Opioid Analgesics; Opioid Receptor; Overdose; Pain; Pathway interactions; Perception; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Physical Dependence; Physiological; Property; Publishing; Rattus; Receptor Signaling; Recruitment Activity; Regulation; Research; Services; Signal Pathway; Signal Transduction; Site; Small Business Innovation Research Grant; Solubility; Structure-Activity Relationship; Symptoms; Technology; Testing; Therapeutic; United States; Validation; Work; analog; base; celecoxib; chemical synthesis; chronic pain; design; drug discovery; esterase; genetic regulatory protein; improved; in vitro testing; in vivo; medical attention; mu opioid receptors; novel; novel strategies; pre-clinical; receptor; receptor internalization; respiratory; safety study; salvinorin A; success

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.

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。拟议的研究旨在开发一种新型的阿片类止痛药，这种止痛药产生的耐受性较低，并可能减少阿片剂相关的副作用。阿片配体激活G蛋白偶联受体，介导多种生理功能。这些受体的调节最终可以决定阿片受体配基的药效程度。缺乏gpcr调节分子成分的转基因小鼠表现出明显的阿片类止痛耐受性减弱。因此，具有非常规受体构象的阿片激动剂可以产生新的止痛药，降低耐受性。最近，丹参甲素的衍生物Herkinorin在体内外被发现是一种有效的选择性Mu阿片受体(MOR)激动剂。二萜化学结构为设计具有不同药理性质的阿片激动剂提供了一种新的先导。这种选择性的MU阿片受体激动剂激活受体，诱导大鼠的抗伤害性感受，但在任何测试条件下都不会诱导ssarrestin 2的募集，也不会诱导受体内化--与所有已知的MOR激动剂不同。这项建议的最终目标是开发新型止痛药，减少止痛耐受性和副作用。我们将通过以下具体目标实现这一目标：1)合成从Herkinorin衍生的阿片配体，以消除酯酶降解位点，改善溶解性，并保持或改善MOR的选择性；以及2)通过测试G蛋白信号转导的有效性和效力，寻找不存在ssarrestin向MOR募集的类似物，有效地激活MoR介导的G蛋白偶联，确定Herkinorin类似物的药理特性。Mencuro治疗公司是由这些化合物的发明者共同创立的，通过开发没有常见阿片副作用的有效的Mu阿片受体激动剂，将这项技术商业化。SARmont公司是一家药物发现和设计公司，由约翰·塔利博士领导，他是Celebrex(注册商标)和其他7种已经上市的NCEs的主要发明者。Mencuro将与SARmont公司签约，提供药物化学服务，特别是在化合物合成、分子设计和构效关系分析方面。门古罗将进行所有的体外测试。这项提案的成功将导致提交第二阶段拨款，重点是进一步优化药物化学的效力和选择性，使用已建立的用于疼痛治疗的哺乳动物模型进行体内验证，以及提交IND所需的临床前安全性研究。 公共卫生相关性： 项目叙述长期和持续的、严重的疼痛是许多紊乱和疾病的结果，每年影响超过8000万成年人。阿片类镇痛剂通过靶向Mu阿片受体(MOR)来阻断痛觉；然而，该受体也介导了不想要的阿片副作用，如耐受性、依赖性、便秘和过量。这项提案的目标是创造出无副作用的止痛药物。