Development of a Peptide-Derived Orally-Active Kappa Opioid Agonist for Peripheral Pain: Preclinical Results in Rats

Kappa-opioid agonists are efficacious in peripheral pain models but suffer from centrally-mediated effects. Derivatives of the tetra-peptide D-Phe-D-Phe-D-Nle-D-Arg-NH2, such as CR665, exhibit high peripheral to central nervous system (CNS) selectivity in analgesic models when administered intraveneously (i.v.); however, they are inactive when administered orally. Application of the JT Pharmaceuticals non-natural amino acid technology to CR665 produced derivatives that exhibit peripheral analgesic activity when dosed orally but do not promote CNS-based effects. Lead compound JT09 demonstrated an agonist selectivity for kappa over mu or delta opioid receptors of >33,400 fold with a peripheral versus central selectivity of 900-fold. To assess pain modulation, a rat writhing model of peripheral pain and a hotplate model of CNS-mediated pain were performed. Results indicate that JT09is as efficacious as morphine in alleviating peripheral pain, while failing to produce undesired CNS-mediated effects. In an operant self-administration procedure where rats pressed a lever to receive an intravenous drug infusion, JT09 failed to maintain lever responding, indicating no abuse liability. In contrast, highly salient rewards readily maintained operant responding. Additionally, JT09 did not promote other CNS-mediated effects associated with opioids (sedation, tolerance, addiction). Thus, we propose that JT09 has potential for development as a novel analgesic. Perspective: This article presents data supporting the analgesic properties of an orally available, peripherally-restricted, kappa-opioid agonist for peripheral pain. A potential out-patient pharmaceutical that acts as efficacious as morphine in alleviating peripheral pain, while failing to produce undesired CNS-mediated effects, could help reduce the current healthcare burden associated with prescription opioids.