Norfenfluramine

Last updated

Norfenfluramine
3-trifluoromethylamphetamine.svg
Norfenfluramine molecule ball from xtal.png
Clinical data
Other names3-Trifluoromethylamphetamine; 3-TFMA; Desethylfenfluramine; JP-92
Identifiers
  • 1-[3-(trifluoromethyl)phenyl]propan-2-amine
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C10H12F3N
Molar mass 203.208 g·mol−1
3D model (JSmol)
  • FC(F)(F)c1cccc(c1)CC(N)C
  • 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 Yes check.svgY
  • Key:MLBHFBKZUPLWBD-UHFFFAOYSA-N Yes check.svgY
   (verify)

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]

Pharmacology

Norfenfluramine acts as a serotonin–norepinephrine releasing agent (SNRA) [3] [1] and as a potent serotonin 5-HT2A, 5-HT2B, and 5-HT2C 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-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. [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-HT2A 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-HT2A receptor agonist than norfenfluramine but produces norfenfluramine as a major active metabolite. [7]

Norfenfluramine has been found to act as an agonist of the trace amine-associated receptor 1 (TAAR1). [8] 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. [8]

Monoamine release of norfenfluramine and related agents (EC50 Tooltip Half maximal effective concentration, nM)
Compound NE Tooltip Norepinephrine DA Tooltip Dopamine 5-HT Tooltip SerotoninRef
Dextroamphetamine 6.6–7.25.8–24.8698–1,765 [9] [10] [11] [12]
Levoamphetamine 9.527.7ND [13] [11] [14] [15]
Dextromethamphetamine 12.3–14.38.5–40.4736–1,292 [9] [16] [11] [17]
Levomethamphetamine 28.54164,640 [9] [11]
Dextroethylamphetamine 28.844.1333.0 [18] [19]
Fenfluramine 739>10,000 (RI)79.3–108 [3] [20] [9] [1]
   Dexfenfluramine 302>10,00051.7 [3] [20] [9] [1]
   Levfenfluramine >10,000>10,000147 [3] [20] [1] [21]
Norfenfluramine 168–1701,900–1,925104 [3] [20] [1] [2]
   Dexnorfenfluramine 72.792459.3 [3] [20] [1]
   Levnorfenfluramine 474>10,000287 [3] [20] [1]
Phentermine 28.8–39.42622,575–3,511 [9] [11] [17]
Chlorphentermine >10,000 (RI)935–2,65018.2–30.9 [9] [17]
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: [22] [3] [20]
Norfenfluramine and related agents at the serotonin 5-HT2 receptors
Compound 5-HT2A 5-HT2B 5-HT2C
Ki (nM) EC50 Tooltip Half-maximal effective concentration (nM) Emax Tooltip Maximal efficacy (%) Ki (nM) EC50 Tooltip Half-maximal effective concentration (nM) Emax Tooltip Maximal efficacy (%) Ki (nM) EC50 Tooltip Half-maximal effective concentration (nM) Emax Tooltip Maximal efficacy (%)
Fenfluramine 5,2164,13115%4,134NDND3,183NDND
   Dexfenfluramine 11,107>10,000ND5,09937938%6,24536280%
   Levofenfluramine 5,4635,27943%5,7131,24847%3,41536084%
Norfenfluramine 2,316NDND52.1NDND557NDND
   Dexnorfenfluramine 1,51663088%11.218.473%32413100%
   Levonorfenfluramine 3,8411,56593%47.835771%8141880%
Phentermine >10,000IA or NDIA or ND>10,000IA or NDIA or ND>10,0001,39466%
Chlorphentermine ND>10,000NDND5,370NDND6,456ND
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] [20] [3]

Related Research Articles

<span class="mw-page-title-main">Fenfluramine</span> Medication used to treat seizures

Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome. It was formerly used as an appetite suppressant in the treatment of obesity, but was discontinued for this use due to cardiovascular toxicity before being repurposed for new indications. Fenfluramine was used for weight loss both alone under the brand name Pondimin and in combination with phentermine commonly known as fen-phen.

<span class="mw-page-title-main">Phentermine</span> Weight loss medication

Phentermine, sold under the brand name Adipex-P among others, is a medication used together with diet and exercise to treat obesity. It is available by itself or as the combination phentermine/topiramate. Phentermine is taken by mouth.

<span class="mw-page-title-main">Phenmetrazine</span> Chemical compound

Phenmetrazine, sold under the brand name Preludin among others, is a stimulant drug first synthesized in 1952 and originally used as an appetite suppressant, but withdrawn from the market in the 1980s due to widespread misuse. It was initially replaced by its analogue phendimetrazine which functions as a prodrug to phenmetrazine, but now it is rarely prescribed, due to concerns of misuse and addiction. Chemically, phenmetrazine is a substituted amphetamine containing a morpholine ring or a substituted phenylmorpholine.

<span class="mw-page-title-main">4-Methylaminorex</span> Group of stereoisomers

4-Methylaminorex is a stimulant drug of the 2-amino-5-aryloxazoline group that was first synthesized in 1960 by McNeil Laboratories. It is also known by its street name "U4Euh" ("Euphoria"). It is banned in many countries as a stimulant. 4-Methylaminorex has effects comparable to methamphetamine but with a longer duration.

<span class="mw-page-title-main">Aminorex</span> Chemical compound

Aminorex, sold under the brand names Menocil and Apiquel among others, is a weight loss (anorectic) stimulant drug. It was withdrawn from the market after it was found to cause pulmonary hypertension (PPH). In the United States, aminorex is a Schedule I controlled substance.

<span class="mw-page-title-main">Chlorphentermine</span> Weight loss medication

Chlorphentermine, sold under the brand names Apsedon, Desopimon, and Lucofen, is a serotonergic appetite suppressant of the amphetamine family. Developed in 1962, it is the para-chloro derivative of the better-known appetite suppressant phentermine, which is still in current use.

<span class="mw-page-title-main">Etilamfetamine</span> Chemical compound

Etilamfetamine, also known as N-ethylamphetamine and formerly sold under the brand names Apetinil and Adiparthrol, is a stimulant drug of the amphetamine family. It was invented in the early 20th century and was subsequently used as an anorectic or appetite suppressant in the 1950s, but was not as commonly used as other amphetamines such as amphetamine, methamphetamine, and benzphetamine, and was largely discontinued once newer drugs such as phenmetrazine were introduced.

<span class="mw-page-title-main">Propylamphetamine</span> Chemical compound

Propylamphetamine is a psychostimulant of the amphetamine family which was never marketed. It was first developed in the 1970s, mainly for research into the metabolism of, and as a comparison tool to, other amphetamines.

<span class="mw-page-title-main">Naphthylaminopropane</span> Chemical compound

Naphthylaminopropane, also known as naphthylisopropylamine (NIPA), is an experimental drug that was under investigation for the treatment of alcohol and stimulant addiction.

<span class="mw-page-title-main">5-Fluoro-AMT</span> Chemical compound

5-Fluoro-α-methyltryptamine, also known as PAL-212 or PAL-544, is a putative stimulant, entactogen, and psychedelic tryptamine derivative related to α-methyltryptamine (αMT).

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitters and hence enhanced signaling by those neurotransmitters. The monoamine neurotransmitters include serotonin, norepinephrine, and dopamine; MRAs can induce the release of one or more of these neurotransmitters.

<span class="mw-page-title-main">Dopamine releasing agent</span> Type of drug

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain.

A serotonin–dopamine releasing agent (SDRA) is a type of drug which induces the release of serotonin and dopamine in the body and/or brain.

<span class="mw-page-title-main">4-Methylmethamphetamine</span> Stimulant and entactogen drug of the amphetamine class

4-Methylmethamphetamine (4-MMA), also known as mephedrine, is a putative stimulant and entactogen drug of the amphetamine family. It acts as a serotonin–norepinephrine–dopamine releasing agent (SNDRA). The drug is the β-deketo analogue of mephedrone and the N-methyl analogue of 4-methylamphetamine (4-MA).

<span class="mw-page-title-main">Substituted cathinone</span> Class of chemical compounds

Substituted cathinones, or simply cathinones, which include some stimulants and entactogens, are derivatives of cathinone. They feature a phenethylamine core with an alkyl group attached to the alpha carbon, and a ketone group attached to the beta carbon, along with additional substitutions. Cathinone occurs naturally in the plant khat whose leaves are chewed as a recreational drug.

<span class="mw-page-title-main">Levofenfluramine</span> Non-marketed drug of the amphetamine class

Levofenfluramine (INN), or (−)-3-trifluoromethyl-N-ethylamphetamine, also known as (−)-fenfluramine or (R)-fenfluramine, is a drug of the amphetamine family that, itself (i.e., in enantiopure form), was never marketed. It is the levorotatory enantiomer of fenfluramine, the racemic form of the compound, whereas the dextrorotatory enantiomer is dexfenfluramine. Both fenfluramine and dexfenfluramine are anorectic agents that have been used clinically in the treatment of obesity (and hence, levofenfluramine has been as well since it is a component of fenfluramine). However, they have since been discontinued due to reports of causing cardiovascular conditions such as valvular heart disease and pulmonary hypertension, adverse effects that are likely to be caused by excessive stimulation of 5-HT2B receptors expressed on heart valves.

<span class="mw-page-title-main">4,4'-Dimethylaminorex</span> Chemical compound

4,4'-Dimethylaminorex, sometimes referred to by the street name "Serotoni", is a psychostimulant and entactogen designer drug related to aminorex, 4-methylaminorex, and pemoline. It was first detected in the Netherlands in December 2012, and has been sold as a designer drug around Europe since mid-2013.

<span class="mw-page-title-main">MDMAR</span> Chemical compound

3',4'-Methylenedioxy-4-methylaminorex (MDMAR) is a recreational designer drug from the substituted aminorex family, with monoamine-releasing effects. It is a potent serotonin–norepinephrine–dopamine releasing agent (SNDRA).

<span class="mw-page-title-main">Butylamphetamine</span> Amphetamine derivative and stimulant

Butylamphetamine is a psychostimulant of the substituted amphetamine family which was never marketed.

<span class="mw-page-title-main">2-Phenylmorpholine</span> Pharmaceutical compound

2-Phenylmorpholine is the parent compound of the substituted phenylmorpholine class of compounds. Examples of 2-phenylmorpholine derivatives include phenmetrazine (3-methyl-2-phenylmorpholine), phendimetrazine ( -3,4-dimethyl-2-phenylmorpholine), and pseudophenmetrazine ( -3-methyl-2-phenylmorpholine), which are monoamine releasing agents (MRAs) and psychostimulants. 2-Phenylmorpholine itself is a potent norepinephrine–dopamine releasing agent (NDRA) and hence may act as a stimulant similarly.

References

  1. 1 2 3 4 5 6 7 8 9 10 Rothman RB, Clark RD, Partilla JS, Baumann MH (June 2003). "(+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters". The Journal of Pharmacology and Experimental Therapeutics. 305 (3): 1191–1199. doi:10.1124/jpet.103.049684. PMID   12649307. S2CID   21164342.
  2. 1 2 Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, et al. (June 2003). "3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro". Molecular Pharmacology. 63 (6): 1223–1229. doi:10.1124/mol.63.6.1223. PMID   12761331. S2CID   839426.
  3. 1 2 3 4 5 6 7 8 9 10 Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID   17017961.
  4. 1 2 3 4 Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, et al. (December 2000). "Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications". Circulation. 102 (23): 2836–2841. doi:10.1161/01.cir.102.23.2836. PMID   11104741.
  5. ↑ Setola V, Dukat M, Glennon RA, Roth BL (July 2005). "Molecular determinants for the interaction of the valvulopathic anorexigen norfenfluramine with the 5-HT2B receptor". Molecular Pharmacology. 68 (1): 20–33. doi:10.1124/mol.104.009266. PMID   15831837. S2CID   30906680.
  6. ↑ "European Medicines Agency recommends withdrawal of benfluorex from the market in European Union" (PDF). European Medicines Agency. 2009-12-18. Archived from the original (PDF) on 2009-12-22.
  7. 1 2 Gumpper RH, Roth BL (January 2024). "Psychedelics: preclinical insights provide directions for future research". Neuropsychopharmacology. 49 (1): 119–127. doi:10.1038/s41386-023-01567-7. PMC   10700551 . PMID   36932180.
  8. 1 2 Lewin AH, Miller GM, Gilmour B (December 2011). "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class". Bioorganic & Medicinal Chemistry. 19 (23): 7044–7048. doi:10.1016/j.bmc.2011.10.007. PMC   3236098 . PMID   22037049.
  9. 1 2 3 4 5 6 7 Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID   11071707.
  10. ↑ Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, et al. (2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology. 38 (4): 552–562. doi:10.1038/npp.2012.204. PMC   3572453 . PMID   23072836.
  11. 1 2 3 4 5 Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN   978-0-470-11790-3. OCLC   181862653. OL   18589888W.
  12. ↑ Glennon RA, Dukat M (2017). "Structure-Activity Relationships of Synthetic Cathinones". Curr Top Behav Neurosci. Current Topics in Behavioral Neurosciences. 32: 19–47. doi:10.1007/7854_2016_41. ISBN   978-3-319-52442-9. PMC   5818155 . PMID   27830576.
  13. ↑ Forsyth AN (22 May 2012). "Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines". ScholarWorks@UNO. Retrieved 4 November 2024.
  14. ↑ Liu Y (28 March 2018). "Structural Determinants for Inhibitor Recognition by the Dopamine Transporter". Duquesne Scholarship Collection. Retrieved 11 December 2024. The most commonly studied DAT substrates are amphetamines, including amphetamine and methamphetamine (Fig. 9). S-(+)-amphetamine releases dopamine with an EC50 of 8.7 nM; the R-(−)-amphetamine is 3-fold weaker, at 27.7 nM (EC50) (Blough, Page et al. 2005). Although weaker, a similar trend is seen for the optical isomers of methamphetamine. S-(+)-methamphetamine releases dopamine with an EC50 of 24.5 nM, while the R-(−)-methamphetamine is 16-fold less active at 416 nM (EC50) (Blough, Page et al. 2005). [...] Blough, B. E., K. M. Page, et al. (2005). "Struture-activity relationship studies of DAT, SERT, and NET releasers." New Perspectives on Neurotransmitter Transporter Pharmacology.
  15. ↑ Blough BE, Page KM, Partilla JS, Budzynski AG, Rothman RB (2005). Structure–activity relationship studies of DAT, SERT, and NET releasers. New Perspectives on Neurotransmitter Transporter Pharmacology. Alexandria, VA.
  16. ↑ Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, et al. (2012). "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology. 37 (5): 1192–1203. doi:10.1038/npp.2011.304. PMC   3306880 . PMID   22169943.
  17. 1 2 3 Partilla JS, Dersch CM, Baumann MH, Carroll FI, Rothman RB (1999). "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substractes". Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc (PDF). NIDA Res Monogr. Vol. 180. pp. 1–476 (252). PMID   11680410. RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). [...]
  18. ↑ Fitzgerald LR, Gannon BM, Walther D, Landavazo A, Hiranita T, Blough BE, et al. (March 2024). "Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones". Neuropharmacology. 245: 109827. doi:10.1016/j.neuropharm.2023.109827. PMC  10842458. PMID   38154512.
  19. ↑ Nicole L (2022). "In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones". ProQuest. Retrieved 5 December 2024. FIGURE 2-6: Release: Effects of the specified test drug on monoamine release by DAT (red circles), NET (blue squares), and SERT (black traingles) in rat brain tissue. [...] EC50 values determined for the drug indicated within the panel. [...]
  20. 1 2 3 4 5 6 7 8 Rothman RB, Baumann MH (May 2009). "Serotonergic drugs and valvular heart disease". Expert Opin Drug Saf. 8 (3): 317–329. doi:10.1517/14740330902931524. PMC   2695569 . PMID   19505264.
  21. ↑ Rothman RB, Baumann MH (July 2002). "Therapeutic and adverse actions of serotonin transporter substrates". Pharmacology & Therapeutics. 95 (1): 73–88. doi:10.1016/s0163-7258(02)00234-6. PMID   12163129.
  22. ↑ Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". Eur J Pharmacol. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID   14612135.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.