KOR agonist functional selectivity in peripheral sensory neurons

描述（由申请人提供）：功能选择性，也称为“偏倚激动作用”，是一个术语，用于描述药物作用于相同受体亚型的能力，以差异方式调节与受体偶联的多个信号级联中的每个信号级联的活性。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，人们对功能选择性的潜力感到非常兴奋，因为它可以振兴药物发现/开发过程。对于介导有益作用的特定信号通路（或特定信号通路模式）具有高效能的配体，以及在导致不良反应的通路上具有最小活性的配体，有望提高治疗效果。然而，制药行业在将配体功能选择性纳入药物发现过程方面进展缓慢，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，工作

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.