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.
Fasciano
J
J
Department of Neurology, Johns Hopkins Medical Institutions, Baltimore, MD 21224, USA.
Steele
T
T
Castagnoli
N
N
Katz
J
J
Ricaurte
G
G
D000818:Animals; D000855:Anorexia / Q000139:chemically induced; D001067:Appetite Depressants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005277:Fenfluramine / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects; D008297:Male; D008694:Methamphetamine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008745:Methylation; D009498:Neurotoxins / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D009584:Nitrogen / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018490:Serotonin Agents / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*
D001067:Appetite Depressants; D009498:Neurotoxins; D018490:Serotonin Agents; D005277:Fenfluramine; D008694:Methamphetamine; D009584:Nitrogen