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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“偏向激动作用”，是用于描述药物作用于相同受体亚型差异调节与受体偶联的多个信号级联中的每一个的活性的能力的术语。功能选择性的潜在机制是基于配体特异性受体构象的形成，所述配体特异性受体构象依赖于配体结构并且具有调节各种细胞信号转导分子的不同能力。现在，人们对功能选择性振兴药物发现/开发过程的潜力感到非常兴奋。预期对介导有益作用的特定信号传导途径（或特定信号传导模式）具有高功效且对导致不良作用的途径具有最小活性的配体具有改善的治疗功效。然而，制药工业在将配体功能选择性纳入药物发现过程中方面进展缓慢，这在很大程度上是因为在生理学相关的细胞系统或体内很少有配体功能选择性的实例。如果成功，工作本文提出的方法将有助于建立抗伤害感受的治疗相关行为模型中信号特异性的相关性。我们建议证明，与抗伤害感受相关的特定信号通路的配体功效可以通过对配体的结构修饰进行微调。在本申请中，我们提出使用U 50，488和Salvinorin-A（Sal-A）作为支架来开发功能选择性类似物，其维持对信号传导的高功效导致抗伤害感受的通路，并使抗伤害感受信号通路的活性最小化。我们的具体目标是1）修饰KOR激动剂Sal-A的结构，和2）修饰KOR激动剂U 50，488的结构，以使MAPK（ERK和JNK）信号传导的功效最小化，同时维持（或增强）激活Gai信号传导的功效。Sal-A和U 50，488的类似物将在合成/评估/重新设计的迭代循环中合成，直到获得具有高KOR亲和力和抗伤害感受功效（Gai信号传导）以及低MAPK信号传导功效（抗-抗伤害感受）的所提出的药理学特征的化合物。将利用离体模型（初级感觉神经元培养物）进行初始疗效评价，该模型可提供体内抗伤害感受疗效的高度可预测性。将进一步测试离体达到功效标准的化合物的抗伤害感受性。在疼痛的补充体内行为模型中的功效。这项工作将是第一个使用生理学方法研究功能选择性配体的结构-活性关系的工作。和治疗相关的模型系统来指导化合物的开发。如果成功，这项工作不仅将确立生理系统中功能选择性的重要性，从而预示着药物开发策略的根本性变化，而且还可能导致具有改善的疼痛治疗特征的新药。