Estimation of affinities and efficacies for kappa-receptor agonists in guinea-pig ileum.
1. Ethylketocyclazocine (EKC) and U50,488H have been employed widely as kappa-receptor agonists in the study of opioid receptor systems. However, the quantification of their agonism in terms of affinities and relative efficacies has not been investigated. 2. In this study, operational model-fitting was used to analyse the effects of irreversible receptor alkylation by beta-chlornaltrexamine (beta-CNA) on the kappa-receptor mediated effects of EKC and U50,488H in the isolated, coaxially stimulated ileum of the guinea-pig. 3. EKC produced monophasic inhibitory concentration-effect curves which were readily amenable to analysis. In contrast U50,488H produced biphasic curves characterized by a higher potency phase of agonism that was susceptible to antagonism by 16-methylcyprenorphine (RX8008M) and a lower potency phase that was apparently non-opioid in nature. 4. Analysis of the kappa-receptor-mediated effects of both agonists indicated that EKC has fifteen fold higher affinity than U50,488H and that the two agonists possess similar intrinsic efficacies.
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Department of Biochemical Sciences, Wellcome Research Laboratories, Beckenham, Kent.
Dougall
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D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D003496:Cyclazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation; D016314:Ethylketocyclazocine; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008954:Models, Biological; D009019:Morphinans / Q000494:pharmacology; D009130:Muscle, Smooth / Q000378:metabolism*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011957:Receptors, Opioid / Q000378:metabolism*; D017473:Receptors, Opioid, kappa
D000700:Analgesics; D009019:Morphinans; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; C051207:16-methylcyprenorphine; D016314:Ethylketocyclazocine; D009271:Naltrexone; C017120:chlornaltrexamine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D003496:Cyclazocine