Chemistry:Norfenfluramine

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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] 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 (EC50, nM)
Compound NE DA 5-HT 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) EC50 (nM) Emax (%) Ki (nM) EC50 (nM) Emax (%) Ki (nM) EC50 (nM) Emax (%)
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]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 "(+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters". The Journal of Pharmacology and Experimental Therapeutics 305 (3): 1191–1199. June 2003. doi:10.1124/jpet.103.049684. PMID 12649307. 
  2. ↑ 2.0 2.1 "3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro". Molecular Pharmacology 63 (6): 1223–1229. June 2003. doi:10.1124/mol.63.6.1223. PMID 12761331. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. https://zenodo.org/record/1235860. 
  4. ↑ 4.0 4.1 4.2 4.3 "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. December 2000. doi:10.1161/01.cir.102.23.2836. PMID 11104741. 
  5. ↑ "Molecular determinants for the interaction of the valvulopathic anorexigen norfenfluramine with the 5-HT2B receptor". Molecular Pharmacology 68 (1): 20–33. July 2005. doi:10.1124/mol.104.009266. PMID 15831837. 
  6. ↑ "European Medicines Agency recommends withdrawal of benfluorex from the market in European Union". European Medicines Agency. 2009-12-18. http://www.emea.europa.eu/pdfs/human/referral/benfluorex/Benfluorex_81503309en.pdf. 
  7. ↑ 7.0 7.1 "Psychedelics: preclinical insights provide directions for future research". Neuropsychopharmacology 49 (1): 119–127. January 2024. doi:10.1038/s41386-023-01567-7. PMID 36932180. 
  8. ↑ "Modulation of 5-HT(2A) receptor-mediated head-twitch behaviour in the rat by 5-HT(2C) receptor agonists". Pharmacol Biochem Behav 69 (3–4): 643–652. 2001. doi:10.1016/s0091-3057(01)00552-4. PMID 11509227. 
  9. ↑ 9.0 9.1 "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class". Bioorganic & Medicinal Chemistry 19 (23): 7044–7048. December 2011. doi:10.1016/j.bmc.2011.10.007. PMID 22037049. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse 39 (1): 32–41. January 2001. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. 
  11. ↑ "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology 38 (4): 552–562. 2013. doi:10.1038/npp.2012.204. PMID 23072836. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 "Dopamine-releasing agents". Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. July 2008. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf. 
  13. ↑ "Structure-Activity Relationships of Synthetic Cathinones". Neuropharmacology of New Psychoactive Substances (NPS). Current Topics in Behavioral Neurosciences. 32. Springer. 2017. pp. 19–47. doi:10.1007/7854_2016_41. ISBN 978-3-319-52442-9. 
  14. ↑ Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines. 22 May 2012. https://scholarworks.uno.edu/td/1436/. Retrieved 4 November 2024. 
  15. ↑ Liu, Yi (28 March 2018). Structural Determinants for Inhibitor Recognition by the Dopamine Transporter. https://dsc.duq.edu/etd/829/. 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.". 
  16. ↑ "Structure–activity relationship studies of DAT, SERT, and NET releasers". New Perspectives on Neurotransmitter Transporter Pharmacology. Alexandria, VA. 2005. 
  17. ↑ "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology 37 (5): 1192–1203. 2012. doi:10.1038/npp.2011.304. PMID 22169943. 
  18. ↑ 18.0 18.1 18.2 "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substrates". Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc. NIDA Res Monogr. 180. 1999. pp. 1–476 (252). https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261. "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). [...]" 
  19. ↑ "Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones". Neuropharmacology 245. March 2024. doi:10.1016/j.neuropharm.2023.109827. PMID 38154512. 
  20. ↑ Nicole, Lauren (2022). "In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones". https://www.proquest.com/openview/a207e98868b4a9c5ac9296fb24abbcd8/. "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. [...]" 
  21. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 21.6 21.7 "Serotonergic drugs and valvular heart disease". Expert Opin Drug Saf 8 (3): 317–329. May 2009. doi:10.1517/14740330902931524. PMID 19505264. 
  22. ↑ "Therapeutic and adverse actions of serotonin transporter substrates". Pharmacology & Therapeutics 95 (1): 73–88. July 2002. doi:10.1016/s0163-7258(02)00234-6. PMID 12163129. 
  23. ↑ "Monoamine transporters and psychostimulant drugs". Eur J Pharmacol 479 (1–3): 23–40. October 2003. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135. 

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