Hedberg M H, Jansen J M, Nordvall G, Hjorth S, Unelius L, Johansson A M
Uppsala University, Uppsala Biomedical Centre, Sweden.
J Med Chem. 1996 Aug 30;39(18):3491-502. doi: 10.1021/jm960188q.
Derivatives of the selective serotonin 5-HT1A receptor agonist (R)-11-hydroxy-10-methylaporphine (2) having various substituents in the C10-position or at the nitrogen have been synthesized from natural morphine or 6-O-acetylcodeine, respectively. The C10-substituents were introduced using efficient Stille or Suzuki cross-coupling reactions. The compounds were evaluated for their affinities to 5-HT1A and dopamine (DA) D1 and D2A receptors in vitro. All compounds tested displayed low (micromolar) affinities to D1 and D2A receptors. In addition, changes in steric bulk and/or electronic properties of the C10-substituent as compared to a C10-methyl group, as well as substitution of the N-methyl group for a hydrogen or a larger N-alkyl group, produced a marked decrease in the affinities to 5-HT1A receptors. Selected compounds that displayed moderate to high affinities to 5-HT1A receptors were evaluated for their ability to stimulate 5-HT1A receptors in vivo. The evaluated compounds behaved as agonists at 5-HT1A receptors, except for the N-propyl analogue of 2, (R)-11-hydroxy-10-methyl-N-propylnoraporphine (23), which displayed weak DA receptor agonism at the doses tested. Hence, the substitution pattern of 2 (a C10-methyl, a C11-hydroxy, and an N-methyl group) appears to be optimal for potent interaction of 10,11-disubstituted (R)-aporphines with 5-HT1A receptors. Modeling of ligand-5-HT1A receptor interactions was performed in an attempt to rationalize the observed affinity data. The binding site model suggests the presence of a "methyl pocket" in the 5-HT1A receptor binding ste. The C11-methoxy-substituted aporphines appear to have a different binding mode compared to 2, implying a different accessibility of these compounds to the "methyl pocket".
分别从天然吗啡或6 - O - 乙酰可待因合成了在C10位或氮原子上具有各种取代基的选择性5 - 羟色胺5 - HT1A受体激动剂（R）- 11 - 羟基 - 10 - 甲基阿朴啡（2）的衍生物。使用高效的Stille或Suzuki交叉偶联反应引入C10 - 取代基。在体外评估了这些化合物对5 - HT1A以及多巴胺（DA）D1和D2A受体的亲和力。所有测试的化合物对D1和D2A受体表现出低（微摩尔）亲和力。此外，与C10 - 甲基相比，C10 - 取代基的空间体积和/或电子性质的变化，以及用氢或更大的N - 烷基取代N - 甲基，导致对5 - HT1A受体的亲和力显著降低。对显示出对5 - HT1A受体具有中度至高亲和力的选定化合物进行了体内刺激5 - HT1A受体能力的评估。除了2的N - 丙基类似物（R）- 11 - 羟基 - 10 - 甲基 - N - 丙基去甲阿朴啡（23）在测试剂量下表现出弱的DA受体激动作用外，评估的化合物在5 - HT1A受体上表现为激动剂。因此，2（一个C10 - 甲基、一个C11 - 羟基和一个N - 甲基）的取代模式似乎对于10,11 - 二取代（R）- 阿朴啡与5 - HT1A受体的有效相互作用是最佳的。进行了配体 - 5 - HT1A受体相互作用的建模，试图使观察到的亲和力数据合理化。结合位点模型表明在5 - HT1A受体结合位点存在一个“甲基口袋”。与2相比，C11 - 甲氧基取代的阿朴啡似乎具有不同的结合模式，这意味着这些化合物对“甲基口袋”的可及性不同。
