Norfenfluramine

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.^[1][2]

Norfenfluramine

Clinical data
Other names	3-Trifluoromethylamphetamine; 3-TFMA; Desethylfenfluramine; JP-92
Identifiers
IUPAC name 1-[3-(trifluoromethyl)phenyl]propan-2-amine
CAS Number	19036-73-8 Y
PubChem CID	15897
IUPHAR/BPS	215
ChemSpider	15108 Y
UNII	CLX07A6ZIY
ChEBI	CHEBI:125411
ChEMBL	ChEMBL1979333
CompTox Dashboard (EPA)	DTXSID60904717
Chemical and physical data
Formula	C10H12F3N
Molar mass	203.208 g·mol−1
3D model (JSmol)	Interactive image
SMILES FC(F)(F)c1cccc(c1)CC(N)C
InChI InChI=1S/C10H12F3N/c1-7(14)5-8-3-2-4-9(6-8)10(11,12)13/h2-4,6-7H,5,14H2,1H3 Y Key:MLBHFBKZUPLWBD-UHFFFAOYSA-N Y
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Pharmacology

Norfenfluramine acts as a serotonin–norepinephrine releasing agent (SNRA)^[3][1] and as a potent serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptor agonist.^[4] Both enantiomers of norfenfluramine are active as monoamine releasing agents, although dexnorfenfluramine is more potent than levonorfenfluramine.^[1] Similarly, both enantiomers are active as serotonin 5-HT₂ receptor agonists, but dexnorfenfluramine is likewise more potent than levonorfenfluramine.^[4]

Norfenfluramine is of similar potency as fenfluramine as a serotonin releaser but is substantially more potent as a norepinephrine and dopamine releaser.^[3][1] The drug is also far more potent than fenfluramine as an agonist of the serotonin 5-HT₂ receptors.^[4]

The action of norfenfluramine on serotonin 5-HT_2B 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.^[5] This side effect led to the withdrawal of fenfluramine as an anorectic medication worldwide and to the withdrawal of benfluorex in Europe.^[6]

In spite of acting as a serotonin 5-HT_2A receptor agonist, norfenfluramine is described as non-hallucinogenic.^[7] However, hallucinations have occasionally been reported with large doses of fenfluramine, which itself is a much weaker serotonin 5-HT_2A receptor agonist than norfenfluramine but produces norfenfluramine as a major active metabolite.^[7] Dexnorfenfluramine produces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents.^[8]

Norfenfluramine has been found to act as an agonist of the trace amine-associated receptor 1 (TAAR1).^[9] Dexnorfenfluramine is a very weak human TAAR1 agonist (43% of maximum in screen at a concentration of 10,000 nM), whereas levonorfenfluramine is inactive as a human TAAR1 agonist.^[9]

Monoamine release of norfenfluramine and related agents (EC₅₀Tooltip Half maximal effective concentration, nM)

Compound	NETooltip Norepinephrine	DATooltip Dopamine	5-HTTooltip Serotonin	Ref
Dextroamphetamine	6.6–7.2	5.8–24.8	698–1,765	[10][11][12][13]
Levoamphetamine	9.5	27.7	ND	[14][12][15][16]
Dextromethamphetamine	12.3–14.3	8.5–40.4	736–1,292	[10][17][12][18]
Levomethamphetamine	28.5	416	4,640	[10][12]
Dextroethylamphetamine	28.8	44.1	333.0	[19][20]
Fenfluramine	739	>10,000 (RI)	79.3–108	[3][21][10][1]
Dexfenfluramine	302	>10,000	51.7	[3][21][10][1]
Levfenfluramine	>10,000	>10,000	147	[3][21][1][22]
Norfenfluramine	168–170	1,900–1,925	104	[3][21][1][2]
Dexnorfenfluramine	72.7	924	59.3	[3][21][1]
Levnorfenfluramine	474	>10,000	287	[3][21][1]
Phentermine	28.8–39.4	262	2,575–3,511	[10][12][18]
Chlorphentermine	>10,000 (RI)	935–2,650	18.2–30.9	[10][18]
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: [23][3][21]

Norfenfluramine and related agents at the serotonin 5-HT₂ receptors

Compound	5-HT2A			5-HT2B			5-HT2C
	Ki (nM)	EC50Tooltip Half-maximal effective concentration (nM)	EmaxTooltip Maximal efficacy (%)	Ki (nM)	EC50Tooltip Half-maximal effective concentration (nM)	EmaxTooltip Maximal efficacy (%)	Ki (nM)	EC50Tooltip Half-maximal effective concentration (nM)	EmaxTooltip Maximal efficacy (%)
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: [4][21][3]