Opioid receptor kappa 1 (commonly referred to as the kappa opioid receptor) (KOR or OPRK1 (gene name))

The kappa opioid receptor (KOR) is a G-protein-coupled receptor that is widely distributed throughout the central and peripheral nervous system. It serves as the primary receptor for endogenous dynorphin peptides and is involved in modulating diverse physiological processes including pain perception, stress responses, mood regulation, dopamine signaling, and immune function. KOR agonists have shown significant therapeutic promise for treating pain disorders, pruritis, neurodegenerative diseases like Alzheimer's and multiple sclerosis, and substance use disorders by reducing the rewarding effects of drugs of abuse. However, clinical development has been limited by dysphoric and sedative side effects associated with central nervous system activation. Recent drug development strategies have focused on creating biased agonists that preferentially activate G-protein signaling over β-arrestin pathways, peripherally restricted ligands, and mixed opioid agonists to dissociate desired therapeutic effects from adverse effects. Currently, nalfurafine is the only marketed KOR-selective agonist, approved in Japan for treating itch, while other compounds remain in preclinical and clinical development stages.

Other names

K-OR-1KOR-1KOP (kappa opioid peptide receptor)KOPrOP2Kappa receptorκ-opioid receptor

Agonism: KOR agonists bind to the receptor and activate Gi/o-protein signaling pathways, resulting in inhibition of adenylate cyclase activity and neuronal function. Dopamine antagonism: KOR activation decreases extracellular dopamine levels in reward-related brain regions, reducing drug-seeking behavior. Antagonism: KOR antagonists block the receptor to prevent endogenous dynorphin signaling. G-protein biased signaling: Selective activation of G-protein-mediated signaling over β-arrestin2 recruitment to separate therapeutic effects from side effects. Heteromeric targeting: Compounds designed to selectively target putative KOR-containing heteromers (KOR-DOR and KOR-MOR) without recruiting β-arrestin. Peripheral restriction: Structural modifications to reduce CNS penetrance and centrally-mediated side effects while maintaining peripheral therapeutic effects.