Vaupel D B, Jasinski D R
Brain Imaging Section, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224, USA.
J Pharmacol Exp Ther. 1997 Nov;283(2):833-42.
l-alpha-Acetyl-N-normethadol (nor-LAAM) and l-alpha-acetyl-N, N-dinormethadol (dinor-LAAM) are active metabolites of the opiate l-alpha-acetylmethadol (LAAM), and they contribute to the prolonged actions of the parent compound. Single doses of nor-LAAM, dinor-LAAM, LAAM, methadone and morphine were given intravenously to the chronic spinal dog to determine acute, single-dose effects and their ability to suppress withdrawal in morphine-dependent dogs. These opioids produced dose-dependent antinociception, decreases in body temperature and pupillary constriction. For these measures, dinor-LAAM was 1.5 to 3 times and nor-LAAM 6 to 12 times as potent as LAAM. Five hours after the acute administration of LAAM or either of the metabolites, a 1-mg/kg dose of naltrexone given intravenously produced withdrawal, indicating the presence of acute physical dependence. In dogs physically dependent on a daily dose of 125 mg of morphine, nor-LAAM was 9 times as potent as either LAAM or dinor-LAAM in suppressing spontaneous withdrawal 40 hr after the last dose of morphine. The efficacies of LAAM and its demethylated metabolites in the dog for producing acute opiate effects were comparable with those of morphine and methadone. There was a trend, however, for LAAM to suppress the expression of abstinence more fully than either metabolite. The usefulness of LAAM as a treatment for opiate addiction is likely due in part to the equivalent efficacies and higher potencies of its nor and dinor metabolites.
左旋 -α- 乙酰 -N- 去甲美沙醇（nor-LAAM）和左旋 -α- 乙酰 -N，N- 二去甲美沙醇（dinor-LAAM）是阿片类药物左旋 -α- 乙酰美沙醇（LAAM）的活性代谢产物，它们导致母体化合物作用时间延长。给慢性脊髓犬静脉注射单剂量的 nor-LAAM、dinor-LAAM、LAAM、美沙酮和吗啡，以确定急性单剂量效应及其抑制吗啡依赖犬戒断反应的能力。这些阿片类药物产生剂量依赖性的镇痛作用、体温下降和瞳孔收缩。就这些指标而言，dinor-LAAM 的效力是 LAAM 的 1.5 至 3 倍，nor-LAAM 的效力是 LAAM 的 6 至 12 倍。急性给予 LAAM 或其任何一种代谢产物 5 小时后，静脉注射 1mg/kg 剂量的纳曲酮会引发戒断反应，表明存在急性身体依赖性。在每日依赖 125mg 吗啡的犬中，在末次给予吗啡 40 小时后，nor-LAAM 在抑制自发戒断方面的效力是 LAAM 或 dinor-LAAM 的 9 倍。LAAM 及其去甲基化代谢产物在犬体内产生急性阿片类效应的效力与吗啡和美沙酮相当。然而，有一个趋势是，LAAM 比其任何一种代谢产物更能充分抑制戒断症状的表现。LAAM 作为阿片类成瘾治疗药物的有效性可能部分归因于其去甲和二去甲代谢产物的等效效力和更高的效能。
