Structural requirements in the reaction of morphine uridine diphosphate glucuronyltransferase with opioid substances.
The influence of the 3-hydroxyl and N-alkyl groups in the reactivity of narcotic compounds with morphine UDP-glucuronyltransferase was studied. Opioids possessing both, one or none of these groups were tested for inhibition of morphine glucuronidation in rabbit liver microsomal preparations. Compounds with only a 3-hydroxyl group (normorphine) or an N-methyl group (codeine, ethylmorphine) were less potent competitive inhibitors than those containing both groups (dextrorphan). Norcodeine, with neither of these groups, had no inhibitory effect. The synthetic narcotics (+)- and (-)-methadone, (-)-alpha-acetylmethadol and meperidine, with only an N-alkyl group, were effective competitive inhibitors. No stereoselectivity of the morphine glucuronyltransferase for opioid isomers was observed, and [methionine]enkephalin does not react with morphine glucuronyltransferase. Differences of pKa values and water/lipid solubility of narcotics could not explain the effects. Results indicate that the N-alkyl group plays a critical role in the interaction of narcotics with the morphine UDP-glucuronyltransferase.
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology; D009020:Morphine; D009022:Morphine Derivatives / Q000494:pharmacology; D009294:Narcotics / Q000378:metabolism*; D011817:Rabbits; D013379:Substrate Specificity
D009022:Morphine Derivatives; D009294:Narcotics; D009020:Morphine; D014453:Glucuronosyltransferase