(+)-Fenfluramine and Its Major Metabolite, (+)-Norfenfluramine, Are Potent Substrates for Norepinephrine Transporters

@article{Rothman2003FenfluramineAI,
  title={(+)-Fenfluramine and Its Major Metabolite, (+)-Norfenfluramine, Are Potent Substrates for Norepinephrine Transporters},
  author={Richard B. Rothman and Robert D. Clark and John S. Partilla and Michael H Baumann},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2003},
  volume={305},
  pages={1191 - 1199}
}
(±)-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… 

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References

SHOWING 1-10 OF 45 REFERENCES

Therapeutic and adverse actions of serotonin transporter substrates.

Indan Analogs of Fenfluramine and Norfenfluramine Have Reduced Neurotoxic Potential

In vitro and in vivo effects of d-fenfluramine: no apparent relation between 5-hydroxytryptamine release and hypophagia.

TLDR
The results show that d-F is a potent 5-HT releaser also in the hypothalamus, one major site of action of the anorexigenic drug.

In vivo criteria to differentiate monoamine reuptake inhibitors from releasing agents: sibutramine is a reuptake inhibitor.

TLDR
Using microdialysis in the hypothalamus of unanesthetized rats, evidence is provided that serotonin- (5-HT) selective and nonselective reuptake inhibitors can be distinguished from the 5-HT-releasing agent fenfluramine by four criteria.

Evidence for Possible Involvement of 5-HT2B Receptors in the Cardiac Valvulopathy Associated With Fenfluramine and Other Serotonergic Medications

TLDR
It is suggested that all clinically available medications with serotonergic activity and their active metabolites be screened for agonist activity at 5-HT2B receptors and that clinicians should consider suspending their use of medications with significant activity at5-HT1B receptors.

Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates. Implications for primary pulmonary hypertension.

TLDR
It is speculated that medications that are 5-HT transporter substrates get translocated into pulmonary cells where, depending on the degree of drug retention, their intrinsic drug toxicity, and individual susceptibility, PPH could develop as a response to high levels of these drugs or metabolites.