KOR agonist functional selectivity in peripheral sensory neurons

说明(申请人提供)：功能选择性，也称为“偏向激动症”，是一个术语，用来描述作用于同一受体亚型的药物以不同方式调节耦合到受体的多个信号级联中的每一个的活性的能力。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，这些受体构象依赖于配体结构，并具有不同的调节各种细胞信号转导分子的能力。现在，人们对功能选择性重振药物发现/开发过程的潜力感到非常兴奋。对于介导有益效果的特定信号通路(或特定信号模式)具有高效率的配体，以及在导致不良反应的通路上具有最低活性的配体，有望提高治疗效果。然而，制药行业将配体功能选择性纳入药物发现过程的速度一直很慢，这在很大程度上是因为在生理相关的细胞系统或体内很少有配体功能选择性的例子。如果成功，这项工作 这里提出的将有助于在抗伤害感觉的治疗相关的行为模型中建立信号特异性的相关性。我们建议证明，与抗伤害性感受相关的特定信号通路的配基有效性可以通过对配基的结构修改来微调。在这个应用中，我们建议使用U50,488和Salvinorin-A(Salvinorin-A，Salvinorin-A)作为支架来开发保持信号高效的功能选择性类似物 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)修改KOR激动剂SAL-A的结构；2)修改KOR激动剂U50,488的结构，以最大限度地减少MAPK(ERK和JNK)信号的作用，同时保持(或增强)GAI信号的激活作用。SAL-A和U50,488的类似物将在合成/评估/重新设计的迭代周期中合成，直到获得具有高KOR亲和力和抗伤害效应(GAI信号)和低MAPK信号效率(抗伤害效应)的化合物。最初的疗效评估将利用体外模型(初级感觉神经元培养)进行，该模型提供了体内抗伤害性效应的高可预测性。达到体外疗效标准的化合物将进一步进行抗伤害感受测试 在补充的体内疼痛行为模型中的有效性。这项工作将首次利用生理学方法研究功能选择性配体的构效关系。 以及与治疗相关的模型系统，以指导化合物的开发。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战略的根本性变化，而且还可能导致治疗疼痛的治疗方案得到改善的新药。

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.