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.
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000305:Adrenal Cortex Hormones / Q000097:blood; D000701:Analgesics, Opioid; D000818:Animals; D001921:Brain / Q000378:metabolism; D004232:Diuretics; D004361:Drug Tolerance; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009294:Narcotics / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism; D017473:Receptors, Opioid, kappa; D019966:Substance-Related Disorders / Q000209:etiology
D000305:Adrenal Cortex Hormones; D000701:Analgesics, Opioid; D004232:Diuretics; D009294:Narcotics; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer