FE200041 (D-Phe-D-Phe-D-Nle-D-Arg-NH2): A peripheral efficacious kappa opioid agonist with unprecedented selectivity.

The side effects typically associated with the clinical profiles of opioid mu-receptor agonists have driven continuing efforts to identify novel efficacious analgesics, including agonists acting at opioid kappa receptors. Unfortunately, the therapeutic potential of kappa agonists seems limited by significant central nervous system side effects. Kappa opioid agonists, however, exhibit potent peripherally mediated antihyperalgesic and antinociceptive effects, suggesting that a peripherally acting kappa agonist may be efficacious in pain control with a more desirable safety profile than that associated with currently available opioids. Here, we report an all D-amino acid tetrapeptide characterized as a novel, highly selective kappa opioid receptor agonist. FE200041 (D-Phe-D-Phe-D-Nle-D-Arg-NH2) showed selectivity for the human kappa opioid receptor of greater than 30,000- and 68,000-fold versus human mu opioid receptor and human delta-opioid receptor receptors, respectively, and efficacious agonist activity using in vitro tissue assays. FE200041 produced local, peripheral antinociception in the hindpaw ipsilateral, but not contralateral, to injection. Antinociceptive effects of FE200041 in the mouse acetic acid writhing assay lasted over 60 min and were antagonized by naloxone and by selective kappa, but not mu, opioid receptor antagonists. FE200041 significantly inhibited acetic acid writhing and inhibited formalin-induced flinching in rats. FE200041 did not elicit sedation or motor impairment after systemic administration at a dose 10-fold higher than that needed to achieve antinociception. FE200041 is thus a potent peripherally restricted opioid kappa agonist with no demonstrable side effects typical of kappa agonists with central nervous system activity and with unprecedented selectivity for the opioid kappa receptor. The pharmacology of this compound suggests the possibility of therapeutic application.