Norfenfluramine

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title: "Norfenfluramine" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public tags: ["3-(trifluoromethyl)phenyl-compounds", "5-ht2a-agonists", "5-ht2b-agonists", "5-ht2c-agonists", "anorectics", "cardiotoxins", "human-drug-metabolites", "monoaminergic-neurotoxins", "psychedelic-phenethylamines", "serotonin-receptor-agonists", "serotonin-norepinephrine-releasing-agents", "substituted-amphetamines", "taar1-agonists"] description: "Never-marketed drug of the amphetamine family" topic_path: "general/3-trifluoromethyl-phenyl-compounds" source: "https://en.wikipedia.org/wiki/Norfenfluramine" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Never-marketed drug of the amphetamine family ::

::data[format=table title="Infobox drug"]

Field	Value
Watchedfields	changed
verifiedrevid	422837453
image	3-trifluoromethylamphetamine.svg
image_class	skin-invert-image
width	250px
image2	Norfenfluramine molecule ball from xtal.png
image_class2	bg-transparent
width2	225px
CAS_number_Ref
CAS_number	19036-73-8
PubChem	15897
IUPHAR_ligand	215
ChemSpiderID_Ref
ChemSpiderID	15108
UNII_Ref
UNII	CLX07A6ZIY
ChEBI	125411
ChEMBL	1979333
synonyms	3-Trifluoromethylamphetamine; 3-TFMA; Desethylfenfluramine; JP-92
IUPAC_name	1-[3-(trifluoromethyl)phenyl]propan-2-amine
C	10
SMILES	FC(F)(F)c1cccc(c1)CC(N)C
StdInChI_Ref
StdInChI	1S/C10H12F3N/c1-7(14)5-8-3-2-4-9(6-8)10(11,12)13/h2-4,6-7H,5,14H2,1H3
StdInChIKey_Ref
StdInChIKey	MLBHFBKZUPLWBD-UHFFFAOYSA-N
::

| Watchedfields = changed | verifiedrevid = 422837453 | drug_name = | image = 3-trifluoromethylamphetamine.svg | image_class = skin-invert-image | width = 250px | caption = | image2 = Norfenfluramine molecule ball from xtal.png | image_class2 = bg-transparent | width2 = 225px | caption2 =

| pronounce = | tradename = | Drugs.com = | MedlinePlus = | licence_CA = | licence_EU = | DailyMedID = | licence_US = | pregnancy_AU = | pregnancy_category = | dependency_liability = | addiction_liability = | routes_of_administration = | class = | ATC_prefix = | ATC_suffix =

| legal_status =

| bioavailability = | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = | duration_of_action = | excretion =

| CAS_number_Ref = | CAS_number = 19036-73-8 | CAS_supplemental = | PubChem = 15897 | PubChemSubstance = | IUPHAR_ligand = 215 | DrugBank = | ChemSpiderID_Ref = | ChemSpiderID = 15108 | UNII_Ref = | UNII = CLX07A6ZIY | KEGG = | ChEBI = 125411 | ChEMBL = 1979333 | NIAID_ChemDB = | PDB_ligand = | synonyms = 3-Trifluoromethylamphetamine; 3-TFMA; Desethylfenfluramine; JP-92

| IUPAC_name = 1-[3-(trifluoromethyl)phenyl]propan-2-amine | C=10 | H=12 | F=3 | N=1 | SMILES = FC(F)(F)c1cccc(c1)CC(N)C | StdInChI_Ref = | StdInChI = 1S/C10H12F3N/c1-7(14)5-8-3-2-4-9(6-8)10(11,12)13/h2-4,6-7H,5,14H2,1H3 | StdInChIKey_Ref = | StdInChIKey = MLBHFBKZUPLWBD-UHFFFAOYSA-N

Norfenfluramine, or 3-trifluoromethylamphetamine, is a never-marketed drug of the amphetamine family and a major active metabolite of the appetite suppressants fenfluramine and benfluorex. The compound is a racemic mixture of two enantiomers with differing activities, dexnorfenfluramine and levonorfenfluramine.

Pharmacology

Norfenfluramine acts as a serotonin–norepinephrine releasing agent (SNRA) and as a potent serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor agonist. Both enantiomers of norfenfluramine are active as monoamine releasing agents, although dexnorfenfluramine is more potent than levonorfenfluramine. Similarly, both enantiomers are active as serotonin 5-HT2 receptor agonists, but dexnorfenfluramine is likewise more potent than levonorfenfluramine.

Norfenfluramine is of similar potency as fenfluramine as a serotonin releaser but is substantially more potent as a norepinephrine and dopamine releaser. The drug is also far more potent than fenfluramine as an agonist of the serotonin 5-HT2 receptors.

The action of norfenfluramine on serotonin 5-HT2B receptors on heart valves leads to a characteristic pattern of heart failure following proliferation of cardiac fibroblasts on the tricuspid valve, known as cardiac fibrosis. This side effect led to the withdrawal of fenfluramine as an anorectic medication worldwide and to the withdrawal of benfluorex in Europe.

In spite of acting as a serotonin 5-HT2A receptor agonist, norfenfluramine is described as non-hallucinogenic. However, hallucinations have occasionally been reported with large doses of fenfluramine, which itself is a much weaker serotonin 5-HT2A receptor agonist than norfenfluramine but produces norfenfluramine as a major active metabolite. Dexnorfenfluramine produces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents.

Norfenfluramine has been found to act as an agonist of the trace amine-associated receptor 1 (TAAR1). Dexnorfenfluramine is a very weak human TAAR1 agonist (43% of maximum in screen at a concentration of 10,000nM), whereas levonorfenfluramine is inactive as a human TAAR1 agonist.

::data[format=table title="{{Nowrap|[[Monoamine releasing agent|Monoamine release]] of norfenfluramine and related agents ({{Abbrlink|EC₅₀|Half maximal effective concentration}}, nM)}}"]

Compound	Ref
Dextroamphetamine	6.6–7.2
Levoamphetamine	9.5
Dextromethamphetamine	12.3–14.3
Levomethamphetamine	28.5
Dextroethylamphetamine	28.8
Fenfluramine	739
Dexfenfluramine	302
Levfenfluramine	10,000
Norfenfluramine	168–170
Dexnorfenfluramine	72.7
Levnorfenfluramine	474
Phentermine	28.8–39.4
Chlorphentermine	10,000 (RI)
Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs:
::

::data[format=table title="{{Nowrap|Norfenfluramine and related agents at the [[serotonin]] [[5-HT2 receptor|5-HT₂ receptor]]s}}"]

Compound	5-HT2A	5-HT2B	5-HT2C	Ki (nM)	(nM)	(%)	Ki (nM)	(nM)	(%)	Ki (nM)	(nM)	(%)
Fenfluramine	5,216	4,131	15%	4,134	ND	ND	3,183	ND	ND
Dexfenfluramine	11,107	10,000	ND	5,099	379	38%	6,245	362	80%
Levofenfluramine	5,463	5,279	43%	5,713	1,248	47%	3,415	360	84%
Norfenfluramine	2,316	ND	ND	52.1	ND	ND	557	ND	ND
Dexnorfenfluramine	1,516	630	88%	11.2	18.4	73%	324	13	100%
Levonorfenfluramine	3,841	1,565	93%	47.8	357	71%	814	18	80%
Phentermine	10,000	IA or ND	IA or ND	10,000	IA or ND	IA or ND	10,000	1,394	66%
Chlorphentermine	ND	10,000	ND	ND	5,370	ND	ND	6,456	ND
Notes: (1) The smaller the Ki or EC50 value, the more avidly the drug binds to or activates the receptor. The higher the Emax value, the more effectively the drug activates the receptor. (2) All values are for human receptors except for the 5-HT2A and 5-HT2C Ki values, which are for the rat receptors. Refs:
::

References

References

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2. (June 2003). "3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro". Molecular Pharmacology.
3. (December 2000). "Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications". Circulation.
4. (July 2005). "Molecular determinants for the interaction of the valvulopathic anorexigen norfenfluramine with the 5-HT2B receptor". Molecular Pharmacology.
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6. (January 2024). "Psychedelics: preclinical insights provide directions for future research". Neuropsychopharmacology.
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13. (July 2008). "Dopamine Transporters: Chemistry, Biology and Pharmacology". Wiley.
14. Liu, Yi. (28 March 2018). "Structural Determinants for Inhibitor Recognition by the Dopamine Transporter".
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16. (2012). "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology.
17. (March 2024). "Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones". Neuropharmacology.
18. Nicole, Lauren. (2022). "In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones".
19. (July 2002). "Therapeutic and adverse actions of serotonin transporter substrates". Pharmacology & Therapeutics.
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