Levofenfluramine

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.[1] It is the levorotatory enantiomer of fenfluramine, the racemic form of the compound, whereas the dextrorotatory enantiomer is dexfenfluramine.[2] 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).[2] However, they have since been discontinued due to reports of causing cardiovascular conditions such as valvular heart disease and pulmonary hypertension,[3] adverse effects that are likely to be caused by excessive stimulation of 5-HT2B receptors expressed on heart valves.[4][5]

Levofenfluramine
Clinical data
ATC code
  • None
Identifiers
  • (2R)-N-ethyl-1-[3-(trifluoromethyl)phenyl]-2-propanamine
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard100.164.235
Chemical and physical data
FormulaC12H16F3N
Molar mass231.262 g·mol−1
3D model (JSmol)
  • FC(F)(F)c1cccc(c1)C[C@H](NCC)C
  • 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/t9-/m1/s1
  • Key:DBGIVFWFUFKIQN-SECBINFHSA-N

Dexfenfluramine is believed to be solely responsible for the appetite suppressant properties of fenfluramine,[2] of which it has been demonstrated to mediate predominantly via activation of postsynaptic 5-HT1B and 5-HT2C receptors[6] through a combination of indirect serotonin releasing agent and direct serotonin receptor agonist activities (the latter of which are mediated fully by its active metabolite dexnorfenfluramine).[7][8][9] Contrarily, levofenfluramine is thought to contribute only to unwanted side effects.[2] Paradoxically, however, it has been shown that levofenfluramine too acts as a relatively potent releaser of serotonin,[10] though with approximately 1/3 of the efficacy of dexfenfluramine.[10] As such, it would be expected to possess some degree of appetite suppressant properties as well, yet it does not.[2][11] A potential explanation as to why levofenfluramine is not similarly an effective anorectic is that it has also been found to behave as a dopamine receptor antagonist,[12] which, as dopamine antagonists like atypical antipsychotics are associated with causing increased appetite and weight gain—effects that their actions on dopamine receptors have been implicated in playing a role in the development of,[13] is an action that could in theory cancel out the hypothetical serotonergically-mediated appetite suppressant effects of the compound. However, this is speculation and has not been proven.

Levonorfenfluramine, an active metabolite of levofenfluramine, is also a fairly potent serotonin releasing agent (with a potency of approximately 1/2 that of norfenfluramine and 1/6 that of dexfenfluramine) and, similarly to dexnorfenfluramine, is a 5-HT2B and 5-HT2C receptor agonist, as well as a somewhat less potent norepinephrine reuptake inhibitor (about 1/2 that of its efficacy as a serotonin releaser).[5][7][10] As such, it likely contributes significantly to the biological activity—though not necessarily appetite suppressant effects—of not only levofenfluramine but of racemic fenfluramine as well. In contrast to levonorfenfluramine, levofenfluramine is virtually inactive as a reuptake inhibitor or releaser of norepinephrine,[10] and neither compound has any effect on dopamine reuptake or release.[10]

See also

References
  1. Chapman and Hall (1996). Dictionary of Organic Compounds. CRC Press. p. 3141. ISBN 978-0-412-54090-5. Retrieved 12 May 2012.
  2. Robert Pool (15 February 2001). Fat: Fighting the Obesity Epidemic. Oxford University Press. p. 184. ISBN 978-0-19-511853-7. Retrieved 12 May 2012.
  3. Seghatol FF, Rigolin VH (September 2002). "Appetite suppressants and valvular heart disease". Current Opinion in Cardiology. 17 (5): 486–92. doi:10.1097/00001573-200209000-00007. PMID 12357124.
  4. Elangbam CS (October 2010). "Drug-induced valvulopathy: an update". Toxicologic Pathology. 38 (6): 837–48. CiteSeerX 10.1.1.1000.286. doi:10.1177/0192623310378027. PMID 20716786. S2CID 20796556.
  5. Rothman RB, Baumann MH, Savage JE, 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): 2836–41. doi:10.1161/01.CIR.102.23.2836. PMID 11104741.
  6. Astrup A (July 2010). "Drug management of obesity--efficacy versus safety". The New England Journal of Medicine. 363 (3): 288–90. doi:10.1056/NEJMe1004076. PMID 20647205.
  7. Rothman RB, Baumann MH (April 2002). "Serotonin releasing agents. Neurochemical, therapeutic and adverse effects". Pharmacology Biochemistry and Behavior. 71 (4): 825–36. doi:10.1016/S0091-3057(01)00669-4. PMID 11888573. S2CID 24296122.
  8. Miller KJ (October 2005). "Serotonin 5-ht2c receptor agonists: potential for the treatment of obesity". Molecular Interventions. 5 (5): 282–91. doi:10.1124/mi.5.5.8. PMID 16249524.
  9. Ni W, Li MW, Thakali K, Fink GD, Watts SW (May 2004). "The fenfluramine metabolite (+)-norfenfluramine is vasoactive". The Journal of Pharmacology and Experimental Therapeutics. 309 (2): 845–52. doi:10.1124/jpet.103.060806. PMID 14752059. S2CID 8056638.
  10. Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–59. doi:10.2174/156802606778249766. PMID 17017961. Archived from the original on 2012-03-03.
  11. James O'Donnell (Pharm. D.); Gopi Doctor Ahuja (30 May 2005). Drug Injury: Liability, Analysis, and Prevention. Lawyers & Judges Publishing Company. p. 306. ISBN 978-0-913875-27-8. Retrieved 12 May 2012.
  12. Balcioglu A, Wurtman RJ (November 1998). "Effects of fenfluramine and phentermine (fen-phen) on dopamine and serotonin release in rat striatum: in vivo microdialysis study in conscious animals". Brain Research. 813 (1): 67–72. doi:10.1016/S0006-8993(98)01003-8. PMID 9824670. S2CID 34370594.
  13. Reynolds GP, Kirk SL (January 2010). "Metabolic side effects of antipsychotic drug treatment--pharmacological mechanisms". Pharmacology & Therapeutics. 125 (1): 169–79. doi:10.1016/j.pharmthera.2009.10.010. PMID 19931306.
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