Properties of a selective kappa agonist, U-50,488H.
U-50,488H has been shown to be a naloxone antagonizable analgesic in rodents. However, the dose of naloxone needed for antagonism is higher than it is for morphine. U-50,488H does not produce physical dependence; however it does produce tolerance upon chronic administration. U-50,488H is cross tolerant with bremazocine but not with morphine. Monkeys trained to discriminate ethylketocyclazocine (EKC) from saline show a complete generalization to U-50,488H but not to morphine. The evaluation of U-50,488H in 3H-EKC site-selective binding indicated that U-50,488H has a high affinity for the kappa receptor (Ki = 114 nM) and a low affinity for the mu receptor (Ki = 6100 nM). The ratio of Ku/Kk was 0.08 for morphine, 0.4 for dynorphin, and 53.5 for U-50,488H. The data suggest that U-50,488H is a selective agonist at the opioid kappa receptor.
D000701:Analgesics, Opioid / Q000378:metabolism; D000818:Animals; D001681:Biological Assay; D003496:Cyclazocine / Q000031:analogs & derivatives / Q000378:metabolism; D004745:Enkephalins / Q000138:chemical synthesis* / Q000494:pharmacology; D016314:Ethylketocyclazocine; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D007202:Indicators and Reagents; D007700:Kinetics; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects
D000701:Analgesics, Opioid; D004745:Enkephalins; D007202:Indicators and Reagents; D011957:Receptors, Opioid; D016314:Ethylketocyclazocine; D003496:Cyclazocine