Objective: The in vivo effects of fenfluramine result from the combined actions of four active molecular entities ( l‐ fenfluramine, d‐ fenfluramine, and the corresponding enantiomers of the primary metabolite norfenfluramine). Each of these compounds has different properties, with cardiovascular toxicity risk being ascribed primarily to the d ‐enantiomers. To determine whether l ‐fenfluramine or l ‐norfenfluramine is a better candidate for development as an enantiomerically pure antiseizure medication, we investigated dose–response and brain/plasma concentration–response relationships for each of the four individual enantiomers in mice. Methods: Antiseizure activity was evaluated in the maximal electroshock (MES) model at the time of peak effect. Neurotoxicity was assessed by determining minimal motor impairment (MMI) in the rotarod test. Median effective dose (ED ₅₀ ), median toxic dose (TD ₅₀ ), median effective concentration (EC ₅₀ ), and median toxic concentration (TC ₅₀ ) in plasma and brain were estimated from dose– and concentration–response curves after administration of each individual enantiomer. Protective indexes (PIs) were estimated based on dose (TD ₅₀ /ED ₅₀ ) and plasma/brain concentrations (TC ₅₀ /EC ₅₀ ). Results: The four enantiomers differed in antiseizure potency and neurotoxic activity. d‐ Norfenfluramine had the highest potency, but it also had the highest toxicity and the lowest PI. Differences in antiseizure potency and toxicity estimated from plasma and brain concentrations were more prominent than those estimated based on dose. l‐ Fenfluramine had greater potency than d‐ fenfluramine and l‐ norfenfluramine, and was overall the compound with the highest PI (6.3 based on dose, 41.6 based on plasma concentrations, and 39.2 based on brain concentrations). Significance: These findings are relevant in determining which enantiomer is most suitable for clinical development as a stereoselectively pure follow‐up compound to the marketed racemic fenfluramine, and indicate that l ‐fenfluramine has superior antiseizure activity over l ‐norfenfluramine in the MES model. This study also illustrates the limitations of relying solely on dose–response curves, and the added value of assessing concentration–response relationships.

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