这项研究的目的是研究d,l-芬氟拉明和d,L-诺芬氟拉明并评估其在血浆和大脑中的浓度与抗惊厥活性之间的关系。D,l-芬氟拉明,D,在小鼠最大电击癫痫发作(MES)测试中评估了1-诺氟氟拉明及其各个对映体。D,l-芬氟拉明,D,还在DBA/2小鼠听觉癫痫发作模型中评估了l-诺芬氟拉明及其单独的l-对映异构体。所有化合物均腹膜内施用。对DBA/2小鼠中试验化合物的脑和血浆浓度进行定量并与抗惊厥活性相关联。在MES测试中,芬氟拉明,诺芬氟拉明及其对映体显示出相当的抗惊厥活性,ED50值在5.1和14.8mg/kg之间。在听源性癫痫模型中,l-诺芬氟拉明的效力是d的9倍,基于ED50,l-芬氟拉明和比l-芬氟拉明更有效15倍(1.2vs.10.2和17.7mg/kg,分别)。所有化合物的脑浓度比血浆高约20倍。根据大脑EC50值,l-诺芬氟拉明比d强7倍,l-芬氟拉明和比l-芬氟拉明更有效的13倍(1940年与13,200和25,400纳克/克,分别)。代谢形成的d的EC50值,L-诺芬氟拉明和L-诺芬氟拉明与相同化合物的脑EC50值相似,这表明,在听源性癫痫模型中,代谢物负责母体化合物的抗癫痫活性。因为有证据表明D-诺芬氟拉明和D,l-芬氟拉明对心血管和代谢的不良影响,它们的l-对映异构体可能是d的更安全的后续化合物,l-芬氟拉明.我们发现,在测试的模型中,l-芬氟拉明和l-诺芬氟拉明的活性与相应的外消旋体相当。根据DBA/2小鼠的结果和其他考虑,L-norfenfluramine似乎是一个特别有吸引力的候选人,作为一种新的进一步评价,对映体纯的抗癫痫药物。
The aim of this study was to investigate the comparative antiseizure activity of the l-enantiomers of d,l-fenfluramine and d,l-norfenfluramine and to evaluate the relationship between their concentration in plasma and brain and anticonvulsant activity. d,l-Fenfluramine, d,l-norfenfluramine and their individual enantiomers were evaluated in the mouse maximal electroshock seizure (MES) test. d,l-Fenfluramine, d,l-norfenfluramine and their individual l-enantiomers were also assessed in the DBA/2 mouse audiogenic seizure model. All compounds were administered intraperitoneally. Brain and plasma concentrations of the test compounds in DBA/2 mice were quantified and correlated with anticonvulsant activity. In the MES test, fenfluramine, norfenfluramine and their enantiomers showed comparable anticonvulsant activity, with ED50 values between 5.1 and 14.8 mg/kg. In the audiogenic seizure model, l-norfenfluramine was 9 times more potent than d,l-fenfluramine and 15 times more potent than l-fenfluramine based on ED50 (1.2 vs. 10.2 and 17.7 mg/kg, respectively). Brain concentrations of all compounds were about 20-fold higher than in plasma. Based on brain EC50 values, l-norfenfluramine was 7 times more potent than d,l-fenfluramine and 13 times more potent than l-fenfluramine (1940 vs. 13,200 and 25,400 ng/g, respectively). EC50 values for metabolically formed d,l-norfenfluramine and l-norfenfluramine were similar to brain EC50 values of the same compounds administered as such, suggesting that, in the audiogenic seizure model, the metabolites were responsible for the antiseizure activity of the parent compounds. Because of the evidence linking d-norfenfluramine to d,l-fenfluramine to cardiovascular and metabolic adverse effects, their l-enantiomers could potentially be safer follow-up compounds to d,l-fenfluramine. We found that, in the models tested, the activity of l-fenfluramine and l-norfenfluramine was comparable to that of the corresponding racemates. Based on the results in DBA/2 mice and other considerations, l-norfenfluramine appears to be a particularly attractive candidate for further evaluation as a novel, enantiomerically pure antiseizure medication.