HZ2, a selective kappa-opioid agonist

Abstract

We analyzed the pharmacological profile of HZ2, a selective κ opioid receptor agonist, with respect to its potential therapeutic value as an analgesic drug. In vitro, HZ2 exhibits selective affinity and high agonist potency at the κ receptor in opioid ligand binding and isolated organ assays. No relevant affinities to other target sites were detected. In the in vivo rodent and rabbit nociception-related models induced either by physical, chemical, or thermal noxious stimuli, HZ2, following systemic administration, shows a strong antinociceptive activity comparable to morphine. In addition, HZ2 exerts a potent action in inflammatory and persistent pain show in the Randall-Selitto and formalin tests, respectively. An unusually long duration of action was seen in the mouse tail-flick test after intravenous or oral administration. Moreover, the compound shows a high oral availability, and in this respect is superior to morphine. A further advantage of HZ2 is comparison to the κ opioid agonist in the absence of dependence liability and respiratory depression. Effects of κ agonists on gastrointestinal functions have been discussed in the literature with some controversy (69,70,35). Reasons for the discrepancies regarding the relative functional significance of opioid receptor types depend on the species investigated, the motility measure used, the time period covered by the experiment, or the gut region examined (30). Nevertheless, the direct comparison of HZ2 and morphine in the charcoal intestinal passage and PGE2-induced diarrhea tests in mice revealed that the constipational potential of HZ2 is approximately 3-fold less than that of morphine. The sedation, diuresis, and saluresis produced by HZ2 at doses close to the antinociceptive dose are consistent with the expected profile for a κ receptor agonist (15,34,35,67,45). The dose- dependent emesis, also seen in the antinociceptive dose range, is not a typical κ receptor mediated effect, but may be related to the special chemical structure of the compound. In conclusion, HZ2 exhibits strong antinociceptive properties with a potency comparable to morphine. HZ2 possesses a typical κ-agonistic profile, exhibiting a panel of positive and negative activities: it has no morphine-type physical dependence or respiratory depression, but does produce diuresis and sedation. Morphine and related opioids currently provide the mainstay of analgesic therapy for severe pain. κ-Opioid receptor agonists have been developed to avoid the adverse effects of morphine-like μ-selective analgesics while preserving their analgesic activity. With respect to its antinociceptive efficacy, the κ agonist HZ2 is comparable to morphine. However, the κ-receptor-specific side effects in combination with the drawbacks of κ agonists in clinical studies (induction of dysphoria or psychotomimesis) raise questions as to the therapeutic utility of this pharmacologically interesting compound.