Receptor reserve reflects differential intrinsic efficacy associated with opioid diastereomers
| Autor: | Arthur D. Weissman, Scott Perschke, Sandra P. Welch, Thomas C. Rich, James F. Keefer, Richard D. Carliss |
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| Rok vydání: | 2009 |
| Předmět: |
Agonist
Oxymorphol Intrinsic activity medicine.drug_class Clinical Biochemistry Receptors Opioid mu CHO Cells Sodium Chloride Pharmacology Toxicology Biochemistry Mice Behavioral Neuroscience chemistry.chemical_compound Cricetulus Cricetinae medicine Animals Humans Receptor Biological Psychiatry Chemistry Chinese hamster ovary cell Stereoisomerism Receptor antagonist Naltrexone Analgesics Opioid DAMGO Oxymorphone medicine.drug |
| Zdroj: | Pharmacology Biochemistry and Behavior. 92:495-502 |
| ISSN: | 0091-3057 |
| DOI: | 10.1016/j.pbb.2009.01.019 |
| Popis: | Structure-activity relationships built around receptor binding or cell-based assays are designed to reveal physiochemical differences between ligands. We hypothesized that agonist receptor reserve may provide a unique approach to distinguish structurally-related agonists exhibiting similar functional characteristics. An intracellular calcium activation assay in Chinese Hamster Ovary (CHO) cells expressing cloned human mu-opioid receptors was developed. We examined two isomers exhibiting indistinguishable receptor binding and in vitro potency profiles. Oxymorphone, a clinically-available congener of codeine has at least two active diastereomeric metabolites (6alpha- and 6beta-oxymorphols) found to be similar for mu-opioid receptor binding affinity (K(d) = 15 versus 14 nM) and calcium activation (EC(50) = 22 versus 14 nM). Calcium activation was then inhibited in CHO cells in a concentration-dependent manner using the irreversible mu-opioid receptor antagonist, beta-funaltrexamine (beta-FNA). Under these conditions, approximately 10-fold greater receptor reserve was found for 6alpha-oxymorphol compared to 6beta-oxymorphol. This difference between the oxymorphols corresponded to a rank order of intrinsic efficacy (Emax): DAMGO > oxymorphone = 6alpha-oxymorphol = oxycodone > 6beta-oxymorphol. In addition, 6alpha-oxymorphol exhibited greater relative potency than the 6beta-oxymorphol in mouse tail-flick, hot-plate and phenylquinone writhing antinociceptive assays, regardless of route of administration. Thus the beta-FNA/calcium model provides a novel, cell-based approach to distinguish structurally related mu-opioid agonists, and in the specific case of the oxymorphols, receptor reserve differences provided a means to bridge functional in vitro and in vivo models. |
| Databáze: | OpenAIRE |
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