Abstract

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.