U-50,488: a selective and structurally novel non-Mu (kappa) opioid agonist.

U-50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide) displays analgesic actions in a variety (thermal, pressure and irritant) of assays in mice and rats. Naloxone and MR-2266 block this analgesic effect; thus it is mediated by opioid receptors. However, when compared to morphine analgesia, the naloxone and MR-2266 pA2 values for U-50,488 analgesia were much lower and higher, respectively. Likewise, although tolerance occurs to both morphine and U-50,488 analgesia, there was no cross-tolerance between these drugs, and U-50,488 does not cause morphine-type physical dependence. These observations suggest that different opioid receptors mediate the analgesic effects of morphine and U-50,488. The effects of U-50,488 appear to be mediated by the so-called kappa opioid receptor. In contrast to U-50,488, other reputed kappa opioid agonists displayed varying degrees of mu agonist (ketazocine and ethylketocyclazocine) and narcotic antagonist (bremazocine) activities. Thus U-50,488 is a more selective kappa agonist. This conclusion is further supported by binding studies; of all compounds tested, U-59,488 displacement of [3H]ethylketocyclazocine binding was uniquely not blocked by high concentrations of dihydromorphine. In addition to analgesia, this selective kappa agonist also causes opioid receptor-mediated sedation, diuresis and corticosteroid elevations. U-50,488 is a useful tool for studying contrasting kappa and mu opioid receptor-mediated effects.