Novel Probes of the Kappa Opioid Receptor: Chemistry, Pharmacology, and Biology

University Of Florida, Gainesville FL

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Abstract

Project Summary We propose to develop new kappa opioid receptor (KOR) agonists that have diverse signaling profiles with the goal of correlating cellular signaling properties to favorable properties (antipruritic, anxiolytic and non-sedating) in mice. The KOR is an attractive drug target because drugs that activate KOR do not lead to overdose or addiction. However, drugs that act at KOR have had their own side effects that have hampered their use clinically. These include diuresis, dysphoria and sedation. Our prior work has introduced new probe compounds that raise the possibility that the therapeutic effects may be separated from the side effects. Compound triazole 1.1 is a potent KOR agonist that activates GTPγS binding in cells and in mouse striatum with the same potency and efficacy as a standard KOR agonist, U50,488H. U50,488 is potent and efficacious at inducing KOR activation across several signaling platforms, including βarrestin2 recruitment. However, triazole 1.1 is far less potent in recruiting βarrestin2 recruitment, and has been shown to be a biased agonist at KOR (bias factor >20). We and others have shown that triazole 1.1 produces antinociception and suppresses pruritis in rodents, yet is devoid of sedating and dysphoria-like properties. Others have shown that triazole 1.1 suppresses oxycodone- induced itch in nonhuman primates and decreases oxycodone self-administration in rats. Therefore, we propose that selective, G protein signaling biased KOR agonists may be a means to preserve desirable effects and avoid side effects. This proposal seeks 5 years of support to generate diverse chemical probes in order to test the extent of this correlation (does biased agonism = less side effects). We introduce two new chemical scaffolds to build upon our already extensive structure-activity relationship collection. We will fully characterize the pharmacological properties of the compounds across functionally diverse cell-based assays with of a goal of identifying compounds capable of fine-tuning KOR responsiveness. Cell-based responses will be validated in mouse models assessing locomotor responses, suppressing pruritis (itch response), diuresis, and measures of anxiolytic-like behaviors to determine that compound maintains the pharmacological profiles in vivo. Compounds will also be tested in combination with morphine. Probe compounds that show favorable behavioral profiles will be used to explore differential KOR signaling in mouse striatum and striatal neurons. Our enthusiastic team consists of established medicinal and synthetic chemists, a structural biologist, and an opioid neuropharmacologist (with both molecular and behavioral pharmacology expertise). The development of pharmacological tools across diverse pharmacophores and correlating their properties with in vivo response profiles will provide guiding evidence of the optimal chemical and pharmacological properties required to refine KOR-targeting therapeutics.