Design and Synthesis of Functionally Selective Kappa Opioid Receptor Ligands

Abstract

The ability of ligands to differentially regulate the activity of signaling pathways coupled to a receptor potentially enables researchers to optimize therapeutically relevant efficacies, while minimizing activity at pathways that lead to adverse effects. Recent studies have demonstrated the functional selectivity of kappa opioid receptor (KOR) ligands acting at KOR expressed by rat peripheral pain sensing neurons. In addition, KOR signaling leading to antinociception and dysphoria occur via different pathways. Based on this information, it can be hypothesized that a functionally selective KOR agonist would allow researchers to optimize signaling pathways leading to antinociception while simultaneously minimizing activity towards pathways that result in dysphoria. In this study, our goal was to alter the structure of U50,488 such that efficacy was maintained for signaling pathways important for antinociception (inhibition of cAMP accumulation) and minimized for signaling pathways that reduce antinociception. Thus, several compounds based on the U50,488 scaffold were designed, synthesized, and evaluated at KORs. Selected analogues were further evaluated for inhibition of cAMP accumulation, activation of extracellular signal-regulated kinase (ERK), and inhibition of calcitonin gene-related peptide release (CGRP). The data obtained demonstrates that modification of the structure of U50,488 changed the signaling pathway regulation. Specifically, we identified three functionally selective KOR ligands (4b, 9u, and 9ac) that inhibit cAMP accumulation, similar to U50,488, but, unlike U50,488, do not activate ERK. In addition, the ability to inhibit CGRP release showed monotonic concentration-response curves, indicating that a pathway leading to nociception is not activated. These data suggest that the efficacy for specific signaling pathways can be finely tuned by structural modifications to a given ligand.