RT Journal Article
SR Electronic
T1 Activation of G-Proteins by Morphine and Codeine Congeners: Insights to the Relevance of <em>O</em>- and <em>N</em>-Demethylated Metabolites at μ- and δ-Opioid Receptors
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 547
OP 554
DO 10.1124/jpet.103.058602
VO 308
IS 2
A1 Thompson, Chad M.
A1 Wojno, Heidi
A1 Greiner, Elisabeth
A1 May, Everette L.
A1 Rice, Kenner C.
A1 Selley, Dana E.
YR 2004
UL http://jpet.aspetjournals.org/content/308/2/547.abstract
AB 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 δ-opioid receptor-mediated G-protein activation using agonist-stimulated guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) 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 δ-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 δ 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. The American Society for Pharmacology and Experimental Therapeutics