The effect of N-methylation on fenfluramine's neurotoxic and pharmacologic actions

N-Methylation separates methamphetamine's neurotoxic and pharmacologic effects. In particular, N-methylation eliminates methamphetamine's neurotoxic activity while preserving its behavioral pharmacologic activity. The purpose of the present studies was to determine whether N-methylation could also be used to separate fenfluramine's neurotoxic and pharmacologic effects. Fenfluramine-induced serotonin neurotoxicity was assessed by measuring serotonin axonal markers 2 weeks after fenfluramine administration. Pharmacologic effects of fenfluramine were assessed by measuring fenfluramine-induced anorexia and fenfluramine discrimination. Both fenfluramine and its N-methylated analog, N-methylfenfluramine, produced dose-related effects in food intake, drug-discrimination and neurotoxicity studies. Although N-methylation reduced the neurotoxic potency of fenfluramine, it also reduced its pharmacologic activity. Neurotoxic potency was reduced 4- to 8-fold (depending on brain region), while pharmacologic potency was reduced 4- to 10-fold (depending on paradigm). Notably, N-methylation did not change the efficacy of fenfluramine as a serotonin neurotoxin, anorectic agent or discrimination stimulus. These results indicate that fenfluramine's behavioral and neurotoxic effects, unlike those of methamphetamine, are not dissociated by N-methylation. Further, the present results suggest that the effectiveness of side-chain nitrogen substitution in separating the behavioral and neurotoxic effects of amphetamine derivatives is strongly influenced by ring substitutions.