Desmethyl metabolites of serotonergic uptake inhibitors are more potent for suppressing canine cataplexy than their parent compounds.
Desmethyl metabolites of serotonergic uptake inhibitors are more potent for suppressing canine cataplexy than their parent compounds.
复制标题
血清素摄取抑制剂的去甲基代谢物比其母体化合物更有效地抑制犬猝倒。
作者：
Nishino,S;Arrigoni,J;Shelton,J;Dement,WC;Mignot,E
我们对犬发作性睡病的一系列药理学研究表明，肾上腺素能系统比多巴胺能和多巴胺能系统更重要地参与了cataepsy的调节。然而，这与在人类患者中获得的数据明显矛盾，所述数据显示长期口服给药肾上腺素能摄取抑制剂如氯丙咪嗪、齐美利定和氟西汀可有效减少卡他汀。为了探索这种差异，我们评估了各种肾上腺素能摄取抑制剂及其活性去甲基代谢产物对犬卡他命的抗卡他命作用。我们发现，去甲基代谢物的抗惊厥作用，这通常是更有效的体外肾上腺素能摄取抑制，是更有效的，比母体化合物的效果更迅速地发展。此外，在测试的10种化合物中，抗惊厥效力与肾上腺素能摄取抑制呈正相关，与肾上腺素能摄取抑制呈负相关。这些结果与我们的假设是一致的，肾上腺素能系统的优先参与控制cataablasts。我们的研究结果还表明，“选择性”多巴胺能摄取抑制剂在人类嗜睡症中的抗惊厥作用可能是由其选择性较低的活性代谢产物介导的。
Our series of pharmacological studies on canine narcolepsy has suggested that the adrenergic systems are more critically involved in the regulation of cataplexy than the serotonergic and dopaminergic systems. This, however, is an apparent contradiction to data obtained in human patients, which show that chronic oral administration of serotonergic uptake inhibitors, such as clomipramine, zimelidine and fluoxetine, is effective in reducing cataplexy. To explore this discrepancy, we have assessed the anticataplectic effects of various serotonergic uptake inhibitors and their active desmethyl metabolites on canine cataplexy. We found that the anticataplectic effect of the desmethyl metabolites, which are usually more potent for in vitro adrenergic uptake inhibition, was more potent and developed more rapidly than the effect of the parent compounds. Furthermore, the anticataplectic potency was positively correlated to the adrenergic uptake inhibition and was negatively correlated with serotonergic uptake inhibition among the 10 compounds tested. These results are consistent with our hypothesis of a preferential involvement of the adrenergic system in the control of cataplexy. Our results also suggest that the anticataplectic effect of "selective" serotonergic uptake inhibitors in human narcolepsy might be mediated by their less selective active metabolites.