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.
Thompson
Chad M
CM
Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA 23298-0524, USA.
Wojno
Heidi
H
Greiner
Elisabeth
E
May
Everette L
EL
Rice
Kenner C
KC
Selley
Dana E
DE
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