U-50,488 - A SELECTIVE AND STRUCTURALLY NOVEL NON-MU-(KAPPA)-OPIOID AGONIST

Abstract

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 [(.sbd.)5,9-diethyl-2-(3-furylmethyl)-2''-hydroxy-6,7-benzomorphan] block this analgesic effect; thus it is mediated by opioid receptors. When compared to morphine analgesia, the naloxone and MR-2266 pA2 values for U-50,488 analgesia were much lower and higher, respectively. 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. Different opioid receptors may 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. In binding studies of all compounds tested, U-50,488 displacement of [3H]ethylketocyclazocine binding was uniquely not blocked by high concentrations of dihydromorphine. 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.