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Estimation of opioid receptor agonist dissociation constants with β‐chlornaltrexamine, an irreversible ligand which also displays agonism
Author(s) -
Leff P.,
Dougall I.G.
Publication year - 1988
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1988.tb16569.x
Subject(s) - agonist , chemistry , receptor , competitive antagonist , agonism , desensitization (medicine) , pharmacology , antagonist , opioid receptor , partial agonist , receptor antagonist , functional selectivity , enkephalin , medicine , biophysics , endocrinology , opioid , biology , biochemistry , politics , political science , law
1 The irreversible opioid receptor antagonist β‐chlornaltrexamine (β‐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 β‐CNA was investigated by use of the competitive antagonist 16‐methylcyprenorphine (RX8008M). Non‐cumulative concentration‐effect curves for β‐CNA were displaced in a non‐parallel fashion indicating that the agonism was mediated by both μ‐ and κ‐receptors. 3 In principle, expression of agonism by an irreversible receptor antagonist could compromise its use in estimating agonist dissociation constants (pK A s) due to desensitization operating in addition to receptor inactivation. For κ‐receptors, this possibility was checked by use of ethylketocyclazocine (EKC) to mimic the agonist effects of β‐CNA and test whether subsequent EKC concentration‐effect curves were displaced. For μ‐receptors it was necessary to perform more involved experiments in which [D‐Ala 2 , MePhe 4 , Gly‐ol 5 ]enkephalin (DAGOL) was used as a standard agonist and its pK A was estimated under different conditions of β‐CNA incubation. 4 These analyses indicated that neither the μ‐ nor the κ‐receptor‐mediated agonism of β‐CNA was associated with appreciable receptor desensitization. In turn it was concluded that the usefulness of β‐CNA as a pharmacological tool for the estimation of μ‐ and κ‐opioid receptor agonist dissociation constants is not compromised by the agonist effects that the compound demonstrates at these receptors.