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(+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters.
J Pharmacol Exp Ther. 2003 Jun; 305(3):1191-9.JP

Abstract

(+/-)-Fenfluramine is an amphetamine analog that was once widely prescribed as an appetite suppressant. Although (+/-)-fenfluramine is no longer clinically available, the mechanisms underlying its anorectic properties are still of interest. Upon peripheral administration, stereoisomers of (+/-)-fenfluramine are N-deethylated to form the metabolites, (+)- and (-)-norfenfluramine. It is well accepted that isomers of (+/-)-fenfluramine and (+/-)-norfenfluramine interact with 5-hydroxytryptamine (serotonin, 5-HT) transporters to release 5-HT from neurons. However, the effects of these drugs on other monoamine transporters are not well characterized. In this study, we examined the interaction of stereoisomers of (+/-)-fenfluramine and (+/-)-norfenfluramine with transporters for 5-HT, norepinephrine (NE), and dopamine (DA). Results from in vitro assays confirmed these drugs are potent substrates for 5-HT transporters: (+)-fenfluramine, (-)-fenfluramine, (+)-norfenfluramine, and (-)-norfenfluramine released [3H]5-HT from synaptosomes with EC50 values of 52, 147, 59, and 287 nM, respectively. Importantly, (+)-fenfluramine and (+)-norfenfluramine released [3H]NE with EC50 values of 302 and 73 nM. Results from in vivo microdialysis experiments showed that intravenous injection of (+)-norfenfluramine elevates extracellular levels of 5-HT, NE, and DA in rat frontal cortex. The effects of (+)-norfenfluramine on NE and DA were antagonized by pretreatment with the NE uptake blocker nisoxetine. In summary, administration of fenfluramines can increase synaptic levels of 5-HT, NE, and DA in the cortex, and (+)-norfenfluramine likely contributes to these effects. Release of NE and DA evoked by (+)-norfenfluramine is at least partly mediated via NE transporters. Our results emphasize the potential involvement of noradrenergic mechanisms in the actions of fenfluramines.

Authors+Show Affiliations

Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 5500 Nathan Shock Dr., P.O. Box 5180, Baltimore, MD 21224, USA. rrothman@intra.nida.nih.govNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12649307

Citation

Rothman, Richard B., et al. "(+)-Fenfluramine and Its Major Metabolite, (+)-norfenfluramine, Are Potent Substrates for Norepinephrine Transporters." The Journal of Pharmacology and Experimental Therapeutics, vol. 305, no. 3, 2003, pp. 1191-9.
Rothman RB, Clark RD, Partilla JS, et al. (+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters. J Pharmacol Exp Ther. 2003;305(3):1191-9.
Rothman, R. B., Clark, R. D., Partilla, J. S., & Baumann, M. H. (2003). (+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters. The Journal of Pharmacology and Experimental Therapeutics, 305(3), 1191-9.
Rothman RB, et al. (+)-Fenfluramine and Its Major Metabolite, (+)-norfenfluramine, Are Potent Substrates for Norepinephrine Transporters. J Pharmacol Exp Ther. 2003;305(3):1191-9. PubMed PMID: 12649307.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - (+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters. AU - Rothman,Richard B, AU - Clark,Robert D, AU - Partilla,John S, AU - Baumann,Michael H, Y1 - 2003/03/20/ PY - 2003/3/22/pubmed PY - 2003/7/8/medline PY - 2003/3/22/entrez SP - 1191 EP - 9 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 305 IS - 3 N2 - (+/-)-Fenfluramine is an amphetamine analog that was once widely prescribed as an appetite suppressant. Although (+/-)-fenfluramine is no longer clinically available, the mechanisms underlying its anorectic properties are still of interest. Upon peripheral administration, stereoisomers of (+/-)-fenfluramine are N-deethylated to form the metabolites, (+)- and (-)-norfenfluramine. It is well accepted that isomers of (+/-)-fenfluramine and (+/-)-norfenfluramine interact with 5-hydroxytryptamine (serotonin, 5-HT) transporters to release 5-HT from neurons. However, the effects of these drugs on other monoamine transporters are not well characterized. In this study, we examined the interaction of stereoisomers of (+/-)-fenfluramine and (+/-)-norfenfluramine with transporters for 5-HT, norepinephrine (NE), and dopamine (DA). Results from in vitro assays confirmed these drugs are potent substrates for 5-HT transporters: (+)-fenfluramine, (-)-fenfluramine, (+)-norfenfluramine, and (-)-norfenfluramine released [3H]5-HT from synaptosomes with EC50 values of 52, 147, 59, and 287 nM, respectively. Importantly, (+)-fenfluramine and (+)-norfenfluramine released [3H]NE with EC50 values of 302 and 73 nM. Results from in vivo microdialysis experiments showed that intravenous injection of (+)-norfenfluramine elevates extracellular levels of 5-HT, NE, and DA in rat frontal cortex. The effects of (+)-norfenfluramine on NE and DA were antagonized by pretreatment with the NE uptake blocker nisoxetine. In summary, administration of fenfluramines can increase synaptic levels of 5-HT, NE, and DA in the cortex, and (+)-norfenfluramine likely contributes to these effects. Release of NE and DA evoked by (+)-norfenfluramine is at least partly mediated via NE transporters. Our results emphasize the potential involvement of noradrenergic mechanisms in the actions of fenfluramines. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/12649307/_+__Fenfluramine_and_its_major_metabolite__+__norfenfluramine_are_potent_substrates_for_norepinephrine_transporters_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12649307 DB - PRIME DP - Unbound Medicine ER -