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NEUROPHARMACOLOGY

Activation of G-Proteins by Morphine and Codeine Congeners: Insights to the Relevance of O- and N-Demethylated Metabolites at µ- and -Opioid Receptors

Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies (C.M.T., H.W., E.L.M., D.E.S.), Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia; and Laboratory of Medicinal Chemistry (E.G., K.C.R.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

Phenotypic differences in analgesic sensitivity to codeine (3-methoxymorphine) results from polymorphisms in cytochrome P450–2D6, which catalyzes O-demethylation of codeine to morphine. However, O-demethylation reportedly is not required for analgesic activity of the 7,8-saturated codeine congeners dihydrocodeine, hydrocodone, and oxycodone. This study determined the potency and efficacy of these compounds and their demethylated derivatives to stimulate µ- and -opioid receptor-mediated G-protein activation using agonist-stimulated guanosine 5'-O-(3-[³⁵S]thio)triphosphate ([³⁵S]GTPS) binding. Results showed that 7,8-saturated codeine congeners were more efficacious than codeine in activating µ-receptors, but only dihydrocodeine was more efficacious at -receptors. Hydrocodone and oxycodone were 10-fold more potent than codeine and dihydrocodeine at either receptor. Morphine-like compounds with a 3-hydroxy group were 30- to 100-fold more potent than their 3-methoxy analogs at the µ-receptor, and these compounds generally exhibited greater efficacy (e.g., morphine produced 2-fold greater maximal stimulation than codeine). Removal of the N-methyl group did not affect efficacy or potency of codeine congeners to activate µ-receptors, whereas this modification generally increased efficacy but decreased potency of morphine congeners. At the receptor, morphine congeners showed greater potency and structure-dependent differences in efficacy compared with codeine congeners, whereas removal of the N-methyl group had effects similar to those observed at the µ-receptor. These results demonstrate that 7,8-saturated codeine congeners are more efficacious than codeine, which may explain their lack of requirement for 3-O-demethylation in vivo. Nonetheless, because all 7,8-saturated codeine congeners were significantly less potent than their morphine derivatives, further research is needed to understand the relationship between metabolism and in vivo activity of these compounds.

Address correspondence to: Dr. Dana E. Selley, Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Medical College of Virginia, Box 980524, 1112 East Clay Street, Richmond, VA 23298-0524. E-mail: deselley{at}hsc.vcu.edu

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