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Identification
NameFenfluramine
Accession NumberDB00574  (APRD00319)
TypeSmall Molecule
GroupsIllicit, Withdrawn
Description

Fenfluramine was withdrawn from the U.S. market in 1997 after reports of heart valve disease and pulmonary hypertension, including a condition known as cardiac fibrosis.

Structure
Thumb
Synonyms
SynonymLanguageCode
FenfluraminaNot AvailableDCIT
FenfluraminumLatinINN
Salts
Name/CAS Structure Properties
Fenfluramine hydrochloride
Thumb
  • InChI Key: ZXKXJHAOUFHNAS-UHFFFAOYNA-N
  • Monoisotopic Mass: 267.100161871
  • Average Mass: 267.718
DBSALT000802
Brand names
NameCompany
AdifaxNot Available
PonderaxNot Available
PondiminNot Available
Brand mixtures
Brand NameIngredients
Fen-phenfenfluramine + phentermine
Categories
CAS number458-24-2
WeightAverage: 231.2573
Monoisotopic: 231.123484132
Chemical FormulaC12H16F3N
InChI KeyDBGIVFWFUFKIQN-UHFFFAOYSA-N
InChI
InChI=1S/C12H16F3N/c1-3-16-9(2)7-10-5-4-6-11(8-10)12(13,14)15/h4-6,8-9,16H,3,7H2,1-2H3
IUPAC Name
ethyl({1-[3-(trifluoromethyl)phenyl]propan-2-yl})amine
SMILES
CCNC(C)CC1=CC(=CC=C1)C(F)(F)F
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassPhenethylamines
Direct parentAmphetamines and Derivatives
Alternative parentsPolyamines; Dialkylamines; Organofluorides; Alkyl Fluorides
Substituentspolyamine; secondary aliphatic amine; secondary amine; organonitrogen compound; amine; organofluoride; organohalogen; alkyl halide; alkyl fluoride
Classification descriptionThis compound belongs to the amphetamines and derivatives. These are organic compounds containing or derived from 1-phenylpropan-2-amine.
Pharmacology
IndicationFor the management of exogenous obesity as a short-term (a few weeks) adjunct in a regimen of weight reduction based on caloric restriction.
PharmacodynamicsUsed to treat obesity, Fenfluramine decreases caloric intake by increasing serotonin levels in the brain's synapses. Fenfluramine acts as a serotonin reuptake inhibitor. It also causes release of serotonin from the synaptosomes. This in turn increases serotonin transmission in the feeding centre of the brain which suppresses appetite.
Mechanism of actionFenfluramine binds to the serotonin reuptake pump. This causes inhbition of serotonin uptake and release of serotonin. The increased levels of serotonin lead to greater serotonin receptor activation which in turn lead to enhancement of serotoninergic transmission in the centres of feeding behavior located in the hypothalamus. This suppresses the appetite for carbohydrates.
AbsorptionFenfluramine is well-absorbed from the gastrointestinal tract, and a maximal anorectic effect is generally seen after 2 to 4 hours.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic.

SubstrateEnzymesProduct
Fenfluramine
norfenfluramineDetails
Route of eliminationNot Available
Half life20 hours
ClearanceNot Available
ToxicityAgitation and drowsiness, confusion, flushing, tremor (or shivering), fever, sweating, abdominal pain, hyperventilation, and dilated non-reactive pupils seem frequent in fenfluramine overdosage. Reflexes may be either exaggerated or depressed and some patients may have rotary nystagmus. Tachycardia may be present, but blood pressure may be normal or only slightly elevated. Convulsions, coma, and ventricular extrasystoles, culminating in ventricular fibrillation, and cardiac arrest, may occur at higher dosages. Less than 5 mg/kg are toxic to humans. Five-ten mg/kg may produce coma and convulsions. Reported single overdoses have ranged from 300 to 2000 mg; the lowest reported fatal dose was a few hundred mg in a small child, and the highest reported nonfatal dose was 1800 mg in an adult. Most deaths were apparently due to respiratory failure and cardiac arrest. Toxic effects will appear within 30 to 60 minutes and may progress rapidly to potentially fatal complications in 90 to 240 minutes. Symptoms may persist for extended periods depending upon the dose ingested.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.9868
Caco-2 permeable + 0.7004
P-glycoprotein substrate Non-substrate 0.5138
P-glycoprotein inhibitor I Non-inhibitor 0.5934
P-glycoprotein inhibitor II Non-inhibitor 0.8383
Renal organic cation transporter Non-inhibitor 0.7404
CYP450 2C9 substrate Non-substrate 0.8506
CYP450 2D6 substrate Substrate 0.8919
CYP450 3A4 substrate Non-substrate 0.6781
CYP450 1A2 substrate Inhibitor 0.8859
CYP450 2C9 substrate Non-inhibitor 0.8616
CYP450 2D6 substrate Inhibitor 0.7253
CYP450 2C19 substrate Non-inhibitor 0.5205
CYP450 3A4 substrate Non-inhibitor 0.5219
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6657
Ames test Non AMES toxic 0.8808
Carcinogenicity Non-carcinogens 0.6397
Biodegradation Not ready biodegradable 0.984
Rat acute toxicity 3.1255 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9666
hERG inhibition (predictor II) Inhibitor 0.7811
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
TabletOral
PricesNot Available
PatentsNot Available
Properties
Stateliquid
Experimental Properties
PropertyValueSource
melting point108-112 °C at 1.20E+01 mm HgNot Available
water solubility412 mg/LNot Available
logP3.36SANGSTER (1993)
Predicted Properties
PropertyValueSource
Water Solubility0.0215ALOGPS
logP3.3ALOGPS
logP3.47ChemAxon
logS-4ALOGPS
pKa (Strongest Basic)10.22ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area12.03 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity59.2 m3·mol-1ChemAxon
Polarizability22.51 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Vincenzo Cannata, Barbara Galbiati, Angelo Spreafico, “Process for manufacturing 1-(3-trifluoromethyl)-phenyl-propan-2-one intermediate in the synthesis of the fenfluramine.” U.S. Patent US5811586, issued August, 1965.

US5811586
General Reference
  1. Roth BL: Drugs and valvular heart disease. N Engl J Med. 2007 Jan 4;356(1):6-9. Pubmed
External Links
ResourceLink
KEGG CompoundC06996
PubChem Compound3337
PubChem Substance46506096
ChemSpider3220
ChEBI5000
ChEMBL
Therapeutic Targets DatabaseDAP001478
PharmGKBPA449592
Drug Product Database1914057
RxListhttp://www.rxlist.com/cgi/generic/fenflur.htm
WikipediaFenfluramine
ATC CodesA08AA02A08AA04
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(47.2 KB)
Interactions
Drug Interactions
Drug
AcetophenazineDecreased anorexic effect, may increase psychotic symptoms
AlimemazineDecreased anorexic effect, may increase psychotic symptoms
ChlorpromazineDecreased anorexic effect, may increase psychotic symptoms
EthopropazineDecreased anorexic effect, may increase psychotic symptoms
FluoxetineRisk of serotoninergic syndrome
FluphenazineDecreased anorexic effect, may increase psychotic symptoms
FluvoxamineRisk of serotoninergic syndrome
GuanethidineFenfluramine may decrease the effect of guanethidine.
Insulin AspartFenfluramine increases the effect of insulin
Insulin DetemirFenfluramine increases the effect of insulin
Insulin GlulisineFenfluramine increases the effect of insulin
IsocarboxazidPossible hypertensive crisis
MesoridazineDecreased anorexic effect, may increase psychotic symptoms
MethdilazineDecreased anorexic effect, may increase psychotic symptoms
MethotrimeprazineDecreased anorexic effect, may increase psychotic symptoms
ParoxetineRisk of serotoninergic syndrome
PerphenazineDecreased anorexic effect, may increase psychotic symptoms
PhenelzinePossible hypertensive crisis
ProchlorperazineDecreased anorexic effect, may increase psychotic symptoms.
PromazineDecreased anorexic effect, may increase psychotic symptoms
PromethazineDecreased anorexic effect, may increase psychotic symptoms.
PropericiazineDecreased anorexic effect, may increase psychotic symptoms.
PropiomazineDecreased anorexic effect, may increase psychotic symptoms
RasagilinePossible hypertensive crisis
ThiethylperazineDecreased anorexic effect, may increase psychotic symptoms
ThioridazineDecreased anorexic effect, may increase psychotic symptoms
TranylcyprominePossible hypertensive crisis
TrifluoperazineDecreased anorexic effect, may increase psychotic symptoms
TriflupromazineDecreased anorexic effect, may increase psychotic symptoms
VenlafaxineRisk of serotoninergic syndrome
Food Interactions
  • Take without regard to meals.

Targets

1. Sodium-dependent serotonin transporter

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Sodium-dependent serotonin transporter P31645 Details

References:

  1. Rothman RB, Zolkowska D, Baumann MH: Serotonin (5-HT) transporter ligands affect plasma 5-HT in rats. Ann N Y Acad Sci. 2008 Oct;1139:268-84. Pubmed
  2. Cosgrove KP, Staley JK, Baldwin RM, Bois F, Plisson C, Al-Tikriti MS, Seibyl JP, Goodman MM, Tamagnan GD: SPECT imaging with the serotonin transporter radiotracer [123I]p ZIENT in nonhuman primate brain. Nucl Med Biol. 2010 Jul;37(5):587-91. Epub 2010 May 6. Pubmed
  3. Xie T, Tong L, McLane MW, Hatzidimitriou G, Yuan J, McCann U, Ricaurte G: Loss of serotonin transporter protein after MDMA and other ring-substituted amphetamines. Neuropsychopharmacology. 2006 Dec;31(12):2639-51. Epub 2006 Jan 25. Pubmed
  4. Johnson GJ, Leis LA, Dunlop PC, Weir EK: The effect of the anorectic agent, d-fenfluramine, and its primary metabolite, d-norfenfluramine, on intact human platelet serotonin uptake and efflux. J Thromb Haemost. 2003 Dec;1(12):2663-8. Pubmed
  5. Rothman RB, Jayanthi S, Wang X, Dersch CM, Cadet JL, Prisinzano T, Rice KC, Baumann MH: High-dose fenfluramine administration decreases serotonin transporter binding, but not serotonin transporter protein levels, in rat forebrain. Synapse. 2003 Dec 1;50(3):233-9. Pubmed

2. 5-hydroxytryptamine receptor 2B

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
5-hydroxytryptamine receptor 2B P41595 Details

References:

  1. Fitzgerald LW, Burn TC, Brown BS, Patterson JP, Corjay MH, Valentine PA, Sun JH, Link JR, Abbaszade I, Hollis JM, Largent BL, Hartig PR, Hollis GF, Meunier PC, Robichaud AJ, Robertson DW: Possible role of valvular serotonin 5-HT receptors in the cardiopathy associated with fenfluramine. Mol Pharmacol. 2000 Jan;57(1):75-81. Pubmed
  2. Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL: Evidence for possible involvement of 5-HT receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000 Dec 5;102(23):2836-41. Pubmed
  3. Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, Rothman RB, Roth BL: 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol Pharmacol. 2003 Jun;63(6):1223-9. Pubmed
  4. Blanpain C, Le Poul E, Parma J, Knoop C, Detheux M, Parmentier M, Vassart G, Abramowicz MJ: Serotonin 5-HT receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension. Cardiovasc Res. 2003 Dec 1;60(3):518-28. Pubmed
  5. Kaumann AJ, Levy FO: 5-hydroxytryptamine receptors in the human cardiovascular system. Pharmacol Ther. 2006 Sep;111(3):674-706. Pubmed
  6. Roth BL: Drugs and valvular heart disease. N Engl J Med. 2007 Jan 4;356(1):6-9. Pubmed

3. 5-hydroxytryptamine receptor 2C

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
5-hydroxytryptamine receptor 2C P28335 Details

References:

  1. Fitzgerald LW, Burn TC, Brown BS, Patterson JP, Corjay MH, Valentine PA, Sun JH, Link JR, Abbaszade I, Hollis JM, Largent BL, Hartig PR, Hollis GF, Meunier PC, Robichaud AJ, Robertson DW: Possible role of valvular serotonin 5-HT receptors in the cardiopathy associated with fenfluramine. Mol Pharmacol. 2000 Jan;57(1):75-81. Pubmed
  2. McCreary AC, Filip M, Cunningham KA: Discriminative stimulus properties of (+/-)-fenfluramine: the role of 5-HT2 receptor subtypes. Behav Neurosci. 2003 Apr;117(2):212-21. Pubmed
  3. Schuhler S, Clark A, Joseph W, Patel A, Lehnen K, Stratford E, Horan TL, Fone KC, Ebling FJ: Involvement of 5-HT receptors in the regulation of food intake in Siberian hamsters. J Neuroendocrinol. 2005 May;17(5):276-85. Pubmed
  4. Miller KJ: Serotonin 5-ht2c receptor agonists: potential for the treatment of obesity. Mol Interv. 2005 Oct;5(5):282-91. Pubmed
  5. Nonogaki K, Nozue K, Oka Y: Hyperphagia alters expression of hypothalamic 5-HT2C and 5-HT1B receptor genes and plasma des-acyl ghrelin levels in Ay mice. Endocrinology. 2006 Dec;147(12):5893-900. Epub 2006 Sep 14. Pubmed

Enzymes

1. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Haritos VS, Ching MS, Ghabrial H, Gross AS, Taavitsainen P, Pelkonen O, Battaglia SE, Smallwood RA, Ahokas JT: Metabolism of dexfenfluramine in human liver microsomes and by recombinant enzymes: role of CYP2D6 and 1A2. Pharmacogenetics. 1998 Oct;8(5):423-32. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11