title: Estimation of opioid receptor agonist dissociation constants with beta-chlornaltrexamine, an irreversible ligand which also displays agonism.
abstract: 1. The irreversible opioid receptor antagonist beta-chlornaltrexamine (beta-CNA) has been shown previously to have agonist activity in the guinea-pig ileum preparation. However, the receptor type or types mediating this effect have not been established. 2. In this study, the agonism of beta-CNA was investigated by use of the competitive antagonist 16-methylcyprenorphine (RX8008M). Non-cumulative concentration-effect curves for beta-CNA were displaced in a non-parallel fashion indicating that the agonism was mediated by both mu- and kappa-receptors. 3. In principle, expression of agonism by an irreversible receptor antagonist could compromise its use in estimating agonist dissociation constants (pKAs) due to desensitization operating in addition to receptor inactivation. For kappa-receptors, this possibility was checked by use of ethylketocyclazocine (EKC) to mimic the agonist effects of beta-CNA and test whether subsequent EKC concentration-effect curves were displaced. For mu-receptors it was necessary to perform more involved experiments in which [D-Ala2, MePhe4, Gly-ol5]enkephalin (DAGOL) was used as a standard agonist and its pKA was estimated under different conditions of beta-CNA incubation. 4. These analyses indicated that neither the mu- nor the kappa-receptor-mediated agonism of beta-CNA was associated with appreciable receptor desensitization. In turn it was concluded that the usefulness of beta-CNA as a pharmacological tool for the estimation of mu- and kappa-opioid receptor agonist dissociation constants is not compromised by the agonist effects that the compound demonstrates at these receptors.
authors.affiliation: Department of Pharmacology 1, Wellcome Research Laboratories, Beckenham, Kent.
authors.forename: P
authors.initials: P
authors.lastname: Leff
authors.forename: I G
authors.initials: IG
authors.lastname: Dougall
mesh_terms: D000818:Animals; D003496:Cyclazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D016314:Ethylketocyclazocine; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009019:Morphinans / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects; D009271:Naltrexone / Q000031:analogs & derivatives*; D009292:Narcotic Antagonists; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu
chemical_list: D004745:Enkephalins; D009019:Morphinans; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C051207:16-methylcyprenorphine; D016314:Ethylketocyclazocine; D009271:Naltrexone; C017120:chlornaltrexamine; D003496:Cyclazocine