Robert T A, Hagardorn A N, Daigneault E A
Mol Pharmacol. 1982 Mar;21(2):315-9.
Optical isomers of methotrimeprazine, an analgesic/neuroleptic, were investigated with respect to their ability to interact with six receptor types or subtypes. Bovine caudate nucleus tissue homogenates provided the dopamine, opiate, and serotonin receptor populations studied in these experiments. The radioligands used in saturation and binding competition experiments were tritiated dopamine, spiperone, dihydromorphine, 5-L-methionine enkephalin, naloxone, and 5-hydroxytryptamine. Saturation experiments verified acceptable performance of these in vitro receptor assay systems and indicated that a one-site binding model was adequate for each of these ligands under the experimental conditions employed. The competition experiments exhibited statistically significant (p less than 0.05) differences in isomeric effects only for dopamine and 5-hydroxytryptamine receptors. The more active isomer, levorotatory methotrimeprazine, was shown to be pharmacodynamically equivalent to chlorpromazine at these receptor types. When the magnitude of receptor stereoselectivity is plotted against an estimate of the more active isomer's affinity for that particular receptor, an excellent correlation is observed. This suggests that a high degree of stereoselectivity characterizes a highly specific drug/receptor interaction. These findings are compatible with the conclusion that methotrimeprazine does not produce analgesia via a direct action upon opiate receptors.
对作为一种镇痛药/安定药的三甲丙嗪的光学异构体与六种受体类型或亚型相互作用的能力进行了研究。牛尾状核组织匀浆提供了这些实验中所研究的多巴胺、阿片和5-羟色胺受体群体。在饱和及结合竞争实验中使用的放射性配体有氚化多巴胺、螺哌隆、二氢吗啡、5-L-甲硫氨酸脑啡肽、纳洛酮和5-羟色胺。饱和实验证实了这些体外受体分析系统的可接受性能，并表明在所用实验条件下，单点结合模型适用于这些配体中的每一种。竞争实验仅在多巴胺和5-羟色胺受体的异构效应方面显示出具有统计学意义（p小于0.05）的差异。活性更强的异构体左旋三甲丙嗪在这些受体类型上显示出与氯丙嗪在药效学上相当。当将受体立体选择性的程度与活性更强的异构体对该特定受体的亲和力估计值作图时，观察到良好的相关性。这表明高度的立体选择性是高度特异性药物/受体相互作用的特征。这些发现与三甲丙嗪并非通过对阿片受体的直接作用产生镇痛作用这一结论相符。
