Abstract

The side effects typically associated with the clinical profiles of opioid μ-receptor agonists have driven continuing efforts to identify novel efficacious analgesics, including agonists acting at opioid κ receptors. Unfortunately, the therapeutic potential of κ agonists seems limited by significant central nervous system side effects. κ Opioid agonists, however, exhibit potent peripherally mediated antihyperalgesic and antinociceptive effects, suggesting that a peripherally acting κ 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 κ opioid receptor agonist. FE200041 (d-Phe-d-Phe-d-Nle-d-Arg-NH₂) showed selectivity for the human κ opioid receptor of greater than 30,000- and 68,000-fold versus human μ opioid receptor and human δ-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 κ, but not μ, 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 κ agonist with no demonstrable side effects typical of κ agonists with central nervous system activity and with unprecedented selectivity for the opioid κ receptor. The pharmacology of this compound suggests the possibility of therapeutic application.