norfenfluramine

Norfenfluramine
	IUPAC name 1-[3-(Trifluoromethyl)phenyl]propan-2-amine
	Other names 3-Trifluoromethylamphetamine
Identifiers
CAS number	19036-73-8
PubChem	15897
ChemSpider	15108
IUPHAR ligand	215
Jmol-3D images	Image 1
	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 ; Key: MLBHFBKZUPLWBD-UHFFFAOYSA-N InChI=1/C10H12F3N/c1-7(14)5-8-3-2-4-9(6-8)10(11,12)13/h2-4,6-7H,5,14H2,1H3; Key: MLBHFBKZUPLWBD-UHFFFAOYAR ;
Properties
Molecular formula	C10H12F3N
Molar mass	203.20 g mol−1
	(verify) (what is: /?); Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
	Infobox references

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/10/17 10:23:39」(JST)

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Norfenfluramine, or 3-trifluoromethylamphetamine, is a drug of the amphetamine family which behaves as a serotonin and norepinephrine releasing agent and potent 5-HT_2A, 5-HT_2B, and 5-HT_2C agonist. The action of norfenfluramine on 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.^[1] This side effect led to the withdrawal of fenfluramine as an anorectic agent worldwide, and to the withdrawal of benfluorex in Europe,^[2] as both fenfluramine and benfluorex form norfenfluramine as an active metabolite.

References[edit]

^ Setola, V.; Dukat, M.; Glennon, R. A.; Roth, B. L. (2005). "Molecular Determinants for the Interaction of the Valvulopathic Anorexigen Norfenfluramine with the 5-HT_2B Receptor" (pdf). Molecular Pharmacology 68 (1): 20–33. doi:10.1124/mol.104.009266. PMID 15831837.
^ "European Medicines Agency recommends withdrawal of benfluorex from the market in European Union" (pdf). European Medicines Agency. 2009-12-18.

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English Journal

Development and validation of a single LC-MS/MS assay following SPE for simultaneous hair analysis of amphetamines, opiates, cocaine and metabolites.

Imbert L1, Dulaurent S2, Mercerolle M3, Morichon J4, Lachâtre G5, Gaulier JM6.Author information 1Department of Pharmacology and Toxicology, University Hospital, 2, Avenue Martin-Luther-King, 87042 Limoges Cedex, France. Electronic address: laurent.imbert@unilim.fr.2Department of Pharmacology and Toxicology, University Hospital, 2, Avenue Martin-Luther-King, 87042 Limoges Cedex, France. Electronic address: sylvain.dulaurent@unilim.fr.3Department of Pharmacology and Toxicology, University Hospital, 2, Avenue Martin-Luther-King, 87042 Limoges Cedex, France. Electronic address: mm@shimadzu.fr.4Department of Pharmacology and Toxicology, University Hospital, 2, Avenue Martin-Luther-King, 87042 Limoges Cedex, France. Electronic address: CG@chu-limoges.fr.5Department of Pharmacology and Toxicology, University Hospital, 2, Avenue Martin-Luther-King, 87042 Limoges Cedex, France; Laboratory of Toxicology, Faculty of Pharmacy, 2 rue Docteur Raymond Marcland, 87000 Limoges, France. Electronic address: gerard.lachatre@unilim.fr.6Department of Pharmacology and Toxicology, University Hospital, 2, Avenue Martin-Luther-King, 87042 Limoges Cedex, France. Electronic address: jm-gaulier@unilim.fr.AbstractThe two major challenges in hair analysis are the limited amount of samples usually available and the low targeted concentrations. To overcome these limitations, a liquid chromatography-electrospray-tandem mass spectrometry method (LC-ESI-MS/MS) allowing the simultaneous analysis of 17 amphetamines (amphetamine, BDB, m-CPP, dexfenfluramine, DOB, DOM, ephedrine, MBDB, MDA, MDEA, MDMA, methamphetamine, methylphenidate, 4-MTA, norephedrine, norfenfluramine and PMA), 5 opiates (morphine, codeine, heroin, ethylmorphine, and 6AM), cocaine and 5 metabolites [ecgonine methyl ester (EME), benzoylecgonine (BZE), anhydroecgonine methyl ester (AME), cocaethylene, and norcocaine] has been developed. The validation procedure included linearity, intra-day and inter-day variability and accuracy for 5 days (5 replicates at 3 concentration levels). Proficiency studies were used to check the accuracy of the method. As a result, all amphetamines, opiates and cocaine derivatives were satisfactory identified by 2 MRM transitions in 15min. Calibration curves were performed by a quadratic 1/X weighted regression. The calibration model fits from 0.05 to 10ng/mg. The limits of detection (LODs) range between 0.005 and 0.030ng/mg. Precision has been checked by intra-day and inter-day RSD, and associated relative bias, which were lower than 25% for the limits of quantifications (LOQs) and lower than 20% for the other levels tested. This method was routinely applied to hair samples: two positive results of adult drug addicts are presented.
Forensic science international.Forensic Sci Int.2014 Jan;234:132-8. doi: 10.1016/j.forsciint.2013.11.004. Epub 2013 Nov 15.
The two major challenges in hair analysis are the limited amount of samples usually available and the low targeted concentrations. To overcome these limitations, a liquid chromatography-electrospray-tandem mass spectrometry method (LC-ESI-MS/MS) allowing the simultaneous analysis of 17 amphetamines
PMID 24378313

Evidence for a Role of Transporter-Mediated Currents in the Depletion of Brain Serotonin Induced by Serotonin Transporter Substrates.

Baumann MH, Bulling S, Benaderet TS, Saha K, Ayestas MA, Partilla JS, Ali SF, Stockner T, Rothman RB, Sandtner W, Sitte HH.Author information Medicinal Chemistry Section, Intramural Research Program (IRP), NIDA, NIH, Baltimore, MD, USA.AbstractSerotonin (5-HT) transporter (SERT) substrates like fenfluramine and 3,4-methylenedioxymethamphetamine cause long-term depletion of brain 5-HT, while certain other substrates do not. The 5-HT deficits produced by SERT substrates are dependent upon transporter proteins, but the exact mechanisms responsible are unclear. Here, we compared the pharmacology of several SERT substrates: fenfluramine, d-fenfluramine, 1-(m-chlorophenyl)piperazine (mCPP) and 1-(m-trifluoromethylphenyl)piperainze (TFMPP), to establish relationships between acute drug mechanisms and the propensity for long-term 5-HT depletions. In vivo microdialysis was carried out in rat nucleus accumbens to examine acute 5-HT release and long-term depletion in the same subjects. In vitro assays were performed to measure efflux of [3H]5-HT in rat brain synaptosomes and transporter-mediated ionic currents in SERT-expressing Xenopus oocytes. When administered repeatedly to rats (6 mg/kg, i.p., 4 doses), all drugs produce large sustained elevations in extracellular 5-HT (>5-fold) with minimal effects on dopamine. Importantly, two weeks after dosing, only rats exposed to fenfluramine and d-fenfluramine display depletion of brain 5-HT. All test drugs evoke fluoxetine-sensitive efflux of [3H]5-HT from synaptosomes, but d-fenfluramine and its bioactive metabolite d-norfenfluramine induce significantly greater SERT-mediated currents than phenylpiperazines. Our data confirm that drug-induced 5-HT release probably does not mediate 5-HT depletion. However, the magnitude of transporter-mediated inward current may be a critical factor in the cascade of events leading to 5-HT deficits. This hypothesis warrants further study, especially given the growing popularity of designer drugs that target SERT.Neuropsychopharmacology accepted article preview online, 28 November 2013. doi:10.1038/npp.2013.331.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.Neuropsychopharmacology.2013 Nov 28. doi: 10.1038/npp.2013.331. [Epub ahead of print]
Serotonin (5-HT) transporter (SERT) substrates like fenfluramine and 3,4-methylenedioxymethamphetamine cause long-term depletion of brain 5-HT, while certain other substrates do not. The 5-HT deficits produced by SERT substrates are dependent upon transporter proteins, but the exact mechanisms respo
PMID 24287719

Structural basis for molecular recognition at serotonin receptors.

Wang C, Jiang Y, Ma J, Wu H, Wacker D, Katritch V, Han GW, Liu W, Huang XP, Vardy E, McCorvy JD, Gao X, Zhou XE, Melcher K, Zhang C, Bai F, Yang H, Yang L, Jiang H, Roth BL, Cherezov V, Stevens RC, Xu HE.Author information Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.AbstractSerotonin or 5-hydroxytryptamine (5-HT) regulates a wide spectrum of human physiology through the 5-HT receptor family. We report the crystal structures of the human 5-HT1B G protein-coupled receptor bound to the agonist antimigraine medications ergotamine and dihydroergotamine. The structures reveal similar binding modes for these ligands, which occupy the orthosteric pocket and an extended binding pocket close to the extracellular loops. The orthosteric pocket is formed by residues conserved in the 5-HT receptor family, clarifying the family-wide agonist activity of 5-HT. Compared with the structure of the 5-HT2B receptor, the 5-HT1B receptor displays a 3 angstrom outward shift at the extracellular end of helix V, resulting in a more open extended pocket that explains subtype selectivity. Together with docking and mutagenesis studies, these structures provide a comprehensive structural basis for understanding receptor-ligand interactions and designing subtype-selective serotonergic drugs.
Science (New York, N.Y.).Science.2013 May 3;340(6132):610-4. doi: 10.1126/science.1232807. Epub 2013 Mar 21.
Serotonin or 5-hydroxytryptamine (5-HT) regulates a wide spectrum of human physiology through the 5-HT receptor family. We report the crystal structures of the human 5-HT1B G protein-coupled receptor bound to the agonist antimigraine medications ergotamine and dihydroergotamine. The structures revea
PMID 23519210

Japanese Journal

In vivo incorporation of fenfluramine and norfenfluramine into pigmented and nonpigmented hair of rats measured by HPLC-fluorescence detection

Forensic Toxicology 29(1), 44-50, 2011-01
NAID 120003751805

Chiral HPLC Determination of dl-Fenfluramine and dl-Norfenfluramine in Biological Fluids Using DIB-Cl as a Label

Analytical Sciences/Supplements 17icas(0), i907-i909, 2002
NAID 130005034867

Fluorometric determination of DL-fenfluramine, DL-norfenfluramine and phentermine in plasma by achiral and chiral high-performance liquid chromatography

Journal of chromatography. B, Biomedical sciences and applications 763(1), 79-90, 2001-11-05
NAID 10012257365

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