Merz H, Stockhaus K, Wick H
J Med Chem. 1977 Jun;20(6):844-6. doi: 10.1021/jm00216a023.
The two diastereoisomeric N-tetrahydrofurfurylnoroxymorphones and their hydrochlorides 1a and 1b have been prepared and studied pharmacologically; The N-(R)-tetrahydrofurfuryl derivative 1a proved to be an opioid agonist--antagonist and the N-(S)-tetrahydrofurfuryl derivative 1b a pure antagonist. As an analgesic, 1a is 25 times more potent than morphine, but it does not show morphine-like side effects in mice. In withdrawn morphine-dependent rhesus monkeys, 1a only partially suppresses abstinence. Its therapeutic ratio is exceptionally favorable compared with those of morphine and pentazocine. As antagonists, 1a and 1b have comparable potencies of 0.25 and 0.20 of that of nalorphine, respectively, in vivo. In vitro, however, 1a is 28 times (guinea pig ileum) or 6.5 times (mouse vas deferens) more potent than 1b. The antagonist properties of 1a and 1b were not anticipated according to known structure--activity relationships.
已制备出两种非对映异构的N - 四氢糠基去甲羟吗啡酮及其盐酸盐1a和1b，并进行了药理学研究；N - (R) - 四氢糠基衍生物1a被证明是一种阿片样物质激动 - 拮抗剂，而N - (S) - 四氢糠基衍生物1b是一种纯拮抗剂。作为一种镇痛药，1a的效力是吗啡的25倍，但在小鼠中未表现出类似吗啡的副作用。在戒断吗啡依赖的恒河猴中，1a只能部分抑制戒断反应。与吗啡和喷他佐辛相比，其治疗指数格外有利。作为拮抗剂，在体内1a和1b的效力分别相当于烯丙吗啡的0.25倍和0.20倍。然而，在体外，1a的效力比1b强28倍（豚鼠回肠）或6.5倍（小鼠输精管）。根据已知的构效关系，1a和1b的拮抗特性并未被预期到。
