Design, Synthesis, and Pharmacological Characterization of Novel Kappa Opioid Receptor Agonists via Isosteric Replacement Strategy for Inflammatory Pain

Abstract Pain management remains a critical challenge, with mu opioid receptor (MOR) agonists carrying significant risks of respiratory depression and addiction. Kappa opioid receptor (KOR) agonists offer a promising alternative, but centrally mediated adverse effects such as sedation and dysphoria limit their clinical utility. We synthesized 24 nalfurafine analogues via isosteric replacement of its furan side chain with diverse aromatic moieties. All compounds retained high KOR binding affinity and full agonist efficacy, with most displaying G-protein biased signaling. Compound 10, prioritized based on its pharmacological profile, was inactive in thermal nociception assays at doses up to 10 mg/kg, yet produced potent, KOR-mediated antinociception in the acetic acid writhing assay (ED50 = 0.009 mg/kg) and attenuated colonic hypersensitivity in a TNBS-induced colitis model of chronic visceral pain, without significant hypolocomotion. Pharmacokinetic studies identified compound 10 as a P-glycoprotein substrate with limited brain exposure, consistent with a CNS-sparing profile and preferentially peripheral activity.