Erenburg Natalia, Perucca Emilio, Bechard Jeff, Dube Celine, Weishaupt Nina, Sherrington Robin, Bialer Meir
Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112002, Israel.
Department of Medicine (Austin Health), University of Melbourne, Heidelberg, VIC 3084, Australia.
Int J Mol Sci. 2024 Feb 21;25(5):2522. doi: 10.3390/ijms25052522.
The aim of this study was to investigate the comparative antiseizure activity of the -enantiomers of ,-fenfluramine and ,-norfenfluramine and to evaluate the relationship between their concentration in plasma and brain and anticonvulsant activity. ,-Fenfluramine, ,-norfenfluramine and their individual enantiomers were evaluated in the mouse maximal electroshock seizure (MES) test. ,-Fenfluramine, ,-norfenfluramine and their individual -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 ED values between 5.1 and 14.8 mg/kg. In the audiogenic seizure model, -norfenfluramine was 9 times more potent than ,-fenfluramine and 15 times more potent than -fenfluramine based on ED (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 EC values, -norfenfluramine was 7 times more potent than ,-fenfluramine and 13 times more potent than -fenfluramine (1940 vs. 13,200 and 25,400 ng/g, respectively). EC values for metabolically formed ,-norfenfluramine and -norfenfluramine were similar to brain EC 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 -norfenfluramine to ,-fenfluramine to cardiovascular and metabolic adverse effects, their -enantiomers could potentially be safer follow-up compounds to ,-fenfluramine. We found that, in the models tested, the activity of -fenfluramine and -norfenfluramine was comparable to that of the corresponding racemates. Based on the results in DBA/2 mice and other considerations, -norfenfluramine appears to be a particularly attractive candidate for further evaluation as a novel, enantiomerically pure antiseizure medication.
本研究的目的是调查芬氟拉明和去甲芬氟拉明的对映体的抗癫痫活性，并评估它们在血浆和脑中的浓度与抗惊厥活性之间的关系。在小鼠最大电休克惊厥（MES）试验中评估了芬氟拉明、去甲芬氟拉明及其各自的对映体。还在DBA/2小鼠听源性惊厥模型中评估了芬氟拉明、去甲芬氟拉明及其各自的对映体。所有化合物均腹腔注射给药。对DBA/2小鼠中受试化合物的脑和血浆浓度进行了定量，并将其与抗惊厥活性相关联。在MES试验中，芬氟拉明、去甲芬氟拉明及其对映体显示出相当的抗惊厥活性，ED值在5.1至14.8mg/kg之间。在听源性惊厥模型中，基于ED值（分别为1.2mg/kg与10.2mg/kg和17.7mg/kg），去甲芬氟拉明的效力比芬氟拉明高9倍，比芬氟拉明高15倍。所有化合物的脑浓度比血浆中高约20倍。基于脑EC值，去甲芬氟拉明的效力比芬氟拉明高7倍，比芬氟拉明高13倍（分别为1940ng/g与13200ng/g和25400ng/g）。代谢形成的去甲芬氟拉明和去甲芬氟拉明的EC值与直接给药的相同化合物的脑EC值相似，这表明在听源性惊厥模型中，代谢产物是母体化合物抗惊厥活性的原因。由于有证据表明去甲芬氟拉明与芬氟拉明会导致心血管和代谢不良反应，它们的对映体可能是芬氟拉明更安全的后续化合物。我们发现，在测试的模型中，芬氟拉明和去甲芬氟拉明的活性与相应的外消旋体相当。基于DBA/2小鼠的结果及其他考虑因素，去甲芬氟拉明似乎是作为一种新型的、对映体纯的抗癫痫药物进行进一步评估的特别有吸引力的候选物。
