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.