|Chemical and physical data|
|Molar mass||231.257 g/mol|
|3D model (Jmol)||Interactive image|
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.
Dexfenfluramine is believed to be solely responsible for the appetite suppressant properties of fenfluramine, of which it has been demonstrated to mediate predominantly via activation of postsynaptic 5-HT1B and 5-HT2C receptors 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). Contrarily, levofenfluramine is thought to contribute only to unwanted side effects. Paradoxically, however, it has been shown that levofenfluramine too acts as a relatively potent releaser of serotonin, though with approximately 1/3rd of the efficacy of dexfenfluramine, As such, it would be expected to possess some degree of appetite suppressant properties as well, yet it does not. 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, 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, is an action that could in theory cancel out the hypothetical serotonergically-mediated appetite suppressant effects of the compound. Of course, this is merely 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 1/6th that of dexfenfluramine) and, similarly to dexnorfenfluramine, 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). As such, 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, and neither compound has any effect on dopamine reuptake or release.
- Chapman and Hall (1996). Dictionary of Organic Compounds. CRC Press. p. 3141. ISBN 978-0-412-54090-5. Retrieved 12 May 2012.
- 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.
- 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.
- Elangbam CS (October 2010). "Drug-induced valvulopathy: an update". Toxicologic Pathology. 38 (6): 837–48. doi:10.1177/0192623310378027. PMID 20716786.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.