Norfenfluramine

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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]
Norfenfluramine168–1701,900–1,925104 [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%
Norfenfluramine2,316NDND52.1NDND557NDND
   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]

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". Neuropharmacology of New Psychoactive Substances (NPS). Current Topics in Behavioral Neurosciences. Vol. 32. Springer. pp. 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.
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