Activation of G-proteins by morphine and codeine congeners: insights to the relevance of O- and N-demethylated metabolites at mu- and delta-opioid receptors.
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 mu- and delta-opioid receptor-mediated G-protein activation using agonist-stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTP gamma S) binding. Results showed that 7,8-saturated codeine congeners were more efficacious than codeine in activating mu-receptors, but only dihydrocodeine was more efficacious at delta-receptors. Hydrocodone and oxycodone were approximately 10-fold more potent than codeine and dihydrocodeine at either receptor. Morphine-like compounds with a 3-hydroxy group were approximately 30- to 100-fold more potent than their 3-methoxy analogs at the mu-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 mu-receptors, whereas this modification generally increased efficacy but decreased potency of morphine congeners. At the delta 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 mu-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.
Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA 23298-0524, USA.
Chad M
CM
Thompson
Heidi
H
Wojno
Elisabeth
E
Greiner
Everette L
EL
May
Kenner C
KC
Rice
Dana E
DE
Selley
D000818:Animals; D016466:CHO Cells; D003061:Codeine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D009020:Morphine / Q000737:chemistry / Q000494:pharmacology; D009022:Morphine Derivatives / Q000737:chemistry / Q000494:pharmacology; D009294:Narcotics / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D009022:Morphine Derivatives; D009294:Narcotics; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D009020:Morphine; D019204:GTP-Binding Proteins; C014481:dihydrocodeine; D003061:Codeine