Froimowitz M, Cody V
Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02178.
J Med Chem. 1993 Jul 23;36(15):2219-27. doi: 10.1021/jm00067a019.
Conformational analyses have been performed on several phenothiazine and thioxanthene dopamine antagonists using the MM2-87 program and parameter set. The compounds that were examined are thioridazine (2), methotrimeprazine (3), cis- and trans-chlorprothixene, and a piperidylidene derivative of chlorprothixene. In addition, (+)-2 and (-)-3 were determined by X-ray crystallography to have the R absolute configuration. The above compounds were superimposed onto loxapine, which was used as a template for the previously proposed dopamine D2 receptor ligand model. The conformational properties and receptor affinities of these compounds were found to be entirely consistent with the ligand model. For example, a conformer of (+)-R-2 that is consistent with the ligand model is lower in energy than a consistent conformer for (-)-S-2, which agrees with the higher D2 receptor affinity of the former. Similarly, in agreement with the much higher affinity of (-)-R-3 relative to (+)-S-3, only the former contains a low energy conformer consistent with the ligand model. The ligand model is also consistent with the greater potency of cis-thioxanthenes over the trans isomers. These results emphasize the importance of the correct orientation of the ammonium hydrogen for high affinity at the D2 receptor. The pharmacophore for D2 receptor ligands is compared with a recently proposed pharmacophore for D1 ligands.
使用MM2 - 87程序和参数集对几种吩噻嗪和硫杂蒽多巴胺拮抗剂进行了构象分析。所研究的化合物有硫利达嗪（2）、甲硫达嗪（3）、顺式和反式氯普噻吨，以及氯普噻吨的哌啶亚基衍生物。此外，通过X射线晶体学确定（+）-2和（-）-3具有R绝对构型。将上述化合物与洛沙平叠加，洛沙平用作先前提出的多巴胺D2受体配体模型的模板。发现这些化合物的构象性质和受体亲和力与配体模型完全一致。例如，与配体模型一致的（+）-R-2的一种构象体的能量低于（-）-S-2的一致构象体，这与前者较高的D2受体亲和力相符。同样，与（-）-R-3相对于（+）-S-3高得多的亲和力一致，只有前者含有与配体模型一致的低能量构象体。配体模型也与顺式硫杂蒽类相对于反式异构体的更强效力一致。这些结果强调了铵氢的正确取向对于在D2受体处具有高亲和力的重要性。将D2受体配体的药效基团与最近提出的D1配体的药效基团进行了比较。
