KOR agonist functional selectivity in peripheral sensory neurons

KOR 激动剂在外周感觉神经元中的功能选择性

基本信息

批准号：
9301785
负责人：
WILLIAM P CLARKE
金额：
$ 4.06万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9301785
关键词：
Adenylate Cyclase Adverse drug effect Adverse effects Afferent Neurons Affinity Agonist Analgesics Behavioral Behavioral Assay Behavioral Model Binding Biological Models Cell Culture Techniques Cells Characteristics Coupled Data Development Drug Industry Evaluation Figs - dietary Health Lead Ligands MAPK8 gene Mediating Mitogen-Activated Protein Kinases Modeling Modification Molecular Conformation N-terminal Neurons Opioid Receptor Pain Pain management Pathway interactions Pattern Peripheral Pharmaceutical Preparations Phenotype Phosphotransferases Physiological Primary Cell Cultures Process Rattus Regulation Signal Pathway Signal Transduction Specificity Structure Structure-Activity Relationship System Testing Text Therapeutic Therapeutic Agents Treatment Efficacy Work analog base behavior test drug development drug discovery efficacy evaluation improved in vivo novel therapeutics peripheral pain receptor response salvinorin A scaffold transmission process

项目摘要

DESCRIPTION (provided by applicant): Functional selectivity, also known as "biased agonism", is a term used to describe the ability of drugs, acting at the same receptor subtype, to differentially regulate the activity of each of the multiple signaling cascades coupled to the receptor. The underlying mechanism for functional selectivity is based upon the formation of ligand-specific receptor conformations that are dependent upon ligand structure and that have differential ability to regulate various cellular signal transduction molecules. There is now tremendous excitement over the potential of functional selectivity to revitalize the drug discovery/development process. Ligands with high efficacy for specific signaling pathways (or specific patterns of signaling) that mediate beneficial effects, and with minimal activity at pathways that lead to adverse effects, are expected to have improved therapeutic efficacy. However, the pharmaceutical industry has been slow to incorporate ligand functional selectivity into the drug discovery process in large part because there have been few examples of ligand functional selectivity in physiologically relevant cell systems or in vivo. If successful, the work proposed here will help to establish the relevance of signaling specificity in a therapeutically relevant behavioral model of antinociception. We propose to demonstrate that ligand efficacy for specific signaling pathways associated with antinociception can be finely tuned by structural modifications to a ligand. In this application, we propose to use U50,488 and Salvinorin-A (Sal-A) as scaffolds to develop functionally selective analogs that maintain high efficacy for signaling pathways that lead to antinociception and minimize activity toward anti-antinociceptive signaling pathways. Our specific aims are to 1) modify the structure of the KOR agonist, Sal-A, and 2) modify the structure of the KOR agonist, U50,488, to minimize efficacy for MAPK (ERK and JNK) signaling while maintaining (or enhancing) efficacy for activation of Gai signaling. Analogs of Sal-A and U50,488 will be synthesized in an iterative cycle of synthesis/evaluation/redesign until compounds with the proposed pharmacological characteristics of high KOR affinity and efficacy for antinociception (Gai signaling) and low efficacy for MAPK signaling (anti-antinociceptive) are obtained. Initial efficacy evaluation will be done utilizing an ex vivo model (primary sensory neuron cultures) that provides high predictability of antinociceptive efficacy in vivo. Compounds that reach the efficacy criteria ex vivo will be further tested for antinociceptive efficacy in a complementary in vivo behavioral model of pain. This work will be the first to examine structure-activity relationships of functionally selective ligands using a physiologically- and therapeutically-relevant model system to guide compound development. If successful, this work will not only establish the importance of functional selectivity in physiological systems and thereby herald fundamental changes in drug development strategies, but also may lead to new drugs with improved therapeutic profiles for the treatment of pain.

描述（由申请人提供）：功能选择性，也称为“偏置激动剂”，是一种用来描述以同一受体亚型作用的药物的能力，以差异化调节与受体耦合的每个多重信号级联的活性。功能选择性的基本机制是基于依赖配体结构的配体特异性受体构象的形成，并且具有调节各种细胞信号转导分子的差异能力。现在，人们对功能选择性的潜力振兴药物发现/开发过程引起了极大的兴奋。对介导有益效应的特定信号通路（或特定信号传导模式）具有高疗效的配体，并且在导致不良反应的途径上具有最小的活性，预计将提高治疗功效。然而，制药行业在很大程度上将配体功能选择性纳入药物发现过程的速度很慢，因为在生理上相关的细胞系统或体内，几乎没有配体功能选择性的例子。如果成功，工作这里提出的将有助于在抗伤害感受的治疗相关行为模型中确定信号特异性的相关性。我们建议证明，可以通过对配体的结构修饰来对与抗伤害感受相关的特定信号传导途径的配体功效进行细微调节。在此应用程序中，我们建议使用U50,488和Salvinorin-A（SAL-A）作为脚手架来发展功能性选择性类似物，以维持信号传导的高效率导致抗伤害感受并最大程度地减少对抗抗抗心症信号通路的活性的途径。我们的具体目的是1）修改Kor Agonist，SAL-A和2）修改Kor激动剂U50,488的结构，以最大程度地降低MAPK（ERK和JNK）信号的功效，同时保持（或增强）激活GAI信号的功效。 SAL-A和U50,488的类似物将在合成/评估/重新设计的迭代循环中合成，直到具有高kor亲和力的化合物，并且获得了抗焦神敏感性（GAI信号传导）的功效（GAI信号传导），而MAPK信号（抗抗抗激素）获得了低成效。使用离体模型（主要感觉神经元培养物），将进行初始疗效评估，该模型可在体内提供高度可预测性。达到疗效标准的化合物将进一步测试抗伤害感受辅助体内疼痛行为模型的功效。这项工作将是第一个使用生理学上选择性选择配体的结构活性关系的工作以及与治疗相关的模型系统，以指导复合开发。如果成功的话，这项工作不仅将确定生理系统中功能选择性的重要性，从而使药物开发策略的根本变化预示，而且还可能导致具有改善治疗疗法治疗疼痛的新药。