Pharmacokinetic and pharmacodynamic factors contributing to the convulsant action of β-carboline-3-carboxylic acid esters
Pharmacokinetic and pharmacodynamic factors contributing to the convulsant action of β-carboline-3-carboxylic acid esters
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β-咔啉-3-羧酸酯惊厥作用的药代动力学和药效学因素
DOI：
10.1016/0024-3205(83)90854-8
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发表时间：
1983
期刊：
影响因子：
6.1
通讯作者：
P. Skolnick
中科院分区：
文献类型：
--
作者：
M. Schweri;Joseph V. Martin;W. Mendelson;J. Barrett;S. Paul;P. Skolnick
β-咔啉-3-羧酸甲酯和该化合物的6, 7-二甲氧基-4-乙基衍生物都是啮齿类动物的强效惊厥剂，而β-咔啉-3-羧酸乙酯即使以非常高的剂量给药也不会引起惊厥。这些化合物被大鼠血浆（体外）降解的速率与其作为惊厥药的效力相当。相比之下，3-乙氧羰基-β-咔啉被发现能有效引发松鼠猴（Saimiri sciureus）的强直和阵挛性惊厥。此外，与大鼠相比，猴血浆（体外）中 3-乙氧羰基-β-咔啉的降解率可以忽略不计。在大鼠和猴脑中，GABA 抑制 [3 H] β-乙氧羰基-β-咔啉结合的效力或功效没有观察到显着差异。这些数据强烈表明药代动力学以及药效学因素可能决定这些 β-咔啉-3-羧酸酯的药理学特征。
Both the methyl ester of β-carboline-3-carboxylic acid and the 6, 7-dimethoxy-4-ethyl derivative of this compound are potent convulsants in rodents, while the ethyl ester of β-carboline-3-carboxylic acid does not cause convulsions, even when administered at very high doses. The rate of degradation of these compounds by rat plasma (in vitro) parallels their potencies as convulsants. In contrast, 3-carboethoxy-β-carboline was found to potently elicit tonic and clonic convulsions in the squirrel monkey (Saimiri sciureus). Furthermore, the rate of degradation of 3-carboethoxy-β-carboline in monkey plasma (in vitro) is negligible compared with rats. No significant differences were observed in either the potency or efficacy of GABA to inhibit [3 H] β-carboethoxy-β-carboline binding in rat and monkey brain. These data strongly suggest that pharmacokinetic, as well as pharmacodynamic, factors may determine the pharmacologic profile of these β-carboline-3-carboxylic acid esters.