CR-665

Addiction to conventional opioid pain analgesics is a major societal problem that is increasing at an alarming rate. New drugs to combat the effects of opioid abuse are desperately needed. Kappa-opioid agonists are efficacious in peripheral pain models but suffer from centrally-mediated effects. In this article, we discuss our efforts in developing peripheral kappa-based opioid receptor agonists that have the potential analgesic activity of opioids but do not manifest the negative side-effects of opioid use and abuse. Further, derivatives of the tetra-peptide D-Phe-D-Phe-D-Nle-D-Arg-NH₂, such as CR665, exhibit high peripheral to central selectivity in analgesic models when administered intravenously (i.v.); however, they are inactive when administered orally. Application of our laboratory's proprietary 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 activates the kappa-opioid receptor with EC₅₀s in the low nM range, while agonist selectivity for kappa over other peripheral opioid receptors was >33,400 fold. Results indicate that JT09 is approximately as efficacious as morphine in alleviating peripheral pain, while failing to produce undesired CNS-mediated activity. Additionally, JT09 did not promote other CNS-mediated effects associated with morphine (addiction, sedation, dysphoria, 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 health care burden associated with prescription opioids.

Addiction to conventional opioid pain analgesics is a major societal problem that is increasing at an alarming rate. New drugs to combat the effects of opioid abuse are desperately needed. Kappa-opioid agonists are efficacious in peripheral pain models but suffer from centrally-mediated effects. In this review, we discuss our efforts, as well as other's efforts in developing peripheral kappa-based opioid receptor agonists that have the potential analgesic activity of opioids but do not manifest the negative side-effects of opioid use and abuse. Further, derivatives of the tetra peptide D-Phe-D-Phe-D-Nle-D-Arg-NH₂, such as CR665, exhibit high peripheral to central selectivity in analgesic models when administered intravenously (IV); 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 activates the kappa-opioid receptor with EC50s in the low nM range, while agonist selectivity for kappa over other peripheral opioid receptors was >33,400 fold. Results indicate that JT09 acts as efficacious as morphine in alleviating peripheral pain, while failing to produce undesired CNS-mediated activity. Additionally, JT09 did not promote other CNS-mediated effects associated with morphine (addiction, sedation, dysphoria, tolerance). Thus, we propose that JT09 has potential for development as a novel analgesic.