Hennies H H, Friderichs E, Schneider J
Department of Biochemical Pharmacology, Grünenthal GmbH, Aachen, Fed. Rep. of Germany.
Arzneimittelforschung. 1988 Jul;38(7):877-80.
The influence of replacing the phenolic hydroxyl by the methoxy group on opioid receptor binding, analgesic and antitussive action was investigated in the corresponding couples morphine-codeine, hydromorphone-hydrocodone and O-desmethyltramadol (L 235)-tramadol. Binding was studied on rat whole brain membranes (without cerebellum) with the radioligands dihydromorphine (mu-site), ethylketocyclazocine (k-site), D-Ala2-D-Leu5-enkephalin (delta-site) and naloxone (no selective binding). Analgesia (tail flick) and antitussive action (NH3-vapour induced cough) was investigated in rats and ED50 values 10 min after i.v. application were calculated to compare efficacy. All free hydroxyl compounds had higher opioid receptor affinities than the corresponding methoxy derivatives and were more active at the mu-site. The methoxy derivatives codeine and tramadol only had low affinities lacking selectivity towards mu-, kappa-, or delta-binding. Hydrocodone in contrast showed strong and mu-selective binding. The hydroxy compounds had higher analgesic activity than the methoxy congeners and analgesia appeared to correlate with mu-binding affinity. Codeine and hydrocodone were weaker antitussives than the corresponding hydroxy compounds, whereas no significant difference was found between O-desmethyltramadol and tramadol. Only in the tramadol group the methoxy substitution increased antitussive potency in relation to analgesic potency.
在吗啡-可待因、氢吗啡酮-氢可酮以及O-去甲基曲马多（L 235）-曲马多这几组相应化合物中，研究了用甲氧基取代酚羟基对阿片受体结合、镇痛及镇咳作用的影响。用放射性配体二氢吗啡（μ位点）、乙基酮环唑辛（κ位点）、D-丙氨酸2-D-亮氨酸5-脑啡肽（δ位点）和纳洛酮（无选择性结合）对大鼠全脑膜（不含小脑）进行结合研究。在大鼠中研究了镇痛作用（甩尾法）和镇咳作用（NH₃蒸汽诱导咳嗽），并计算静脉注射10分钟后的ED50值以比较疗效。所有游离羟基化合物的阿片受体亲和力均高于相应的甲氧基衍生物，且在μ位点活性更高。甲氧基衍生物可待因和曲马多的亲和力较低，对μ、κ或δ结合缺乏选择性。相比之下，氢可酮表现出强烈的μ选择性结合。羟基化合物的镇痛活性高于甲氧基同系物，镇痛作用似乎与μ结合亲和力相关。可待因和氢可酮的镇咳作用比相应的羟基化合物弱，而O-去甲基曲马多和曲马多之间未发现显著差异。仅在曲马多组中，甲氧基取代相对于镇痛效力增加了镇咳效力。
