Sanchez E, Del Villar E, Tephly T R
Biochem J. 1978 Jan 1;169(1):173-7. doi: 10.1042/bj1690173.
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.
研究了3-羟基和N-烷基对麻醉性化合物与吗啡UDP-葡萄糖醛酸转移酶反应活性的影响。对具有这两种基团、其中一种基团或没有这两种基团的阿片类药物进行了测试，以检测其对兔肝微粒体制剂中吗啡葡萄糖醛酸化的抑制作用。仅含有3-羟基（去甲吗啡）或N-甲基（可待因、乙基吗啡）的化合物作为竞争性抑制剂的效力低于同时含有这两种基团的化合物（右啡烷）。既不含有这两种基团的去甲可待因没有抑制作用。仅含有N-烷基的合成麻醉药（+）-和（-）-美沙酮、（-）-α-乙酰美沙多和哌替啶是有效的竞争性抑制剂。未观察到吗啡葡萄糖醛酸转移酶对阿片类异构体的立体选择性，且[蛋氨酸]脑啡肽不与吗啡葡萄糖醛酸转移酶发生反应。麻醉药的pKa值和水/脂溶性差异无法解释这些作用。结果表明，N-烷基在麻醉药与吗啡UDP-葡萄糖醛酸转移酶的相互作用中起关键作用。
