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Levofenfluramine
Clinical data
ATC code	None;
Identifiers
	IUPAC name (2R)-N-ethyl-1-[3-(trifluoromethyl)phenyl]-2-propanamine;
CAS Number	37577-24-5 ; 5220-89-3 (HCl);
PubChem CID	65801;
ChemSpider	59217;
UNII	953A94Y45B;
CompTox Dashboard (EPA)	DTXSID60191009 ;
ECHA InfoCard	100.164.235
Chemical and physical data
Formula	C12H16F3N
Molar mass	231.262 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES FC(F)(F)c1cccc(c1)C[C@H](NCC)C;
	InChI 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;

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-HT_2B receptors expressed on heart valves.^[4]^[5]

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-HT_1B and 5-HT_2C 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-HT_2B and 5-HT_2C 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]

References

^ Chapman and Hall (1996). Dictionary of Organic Compounds. CRC Press. p. 3141. ISBN 978-0-412-54090-5. Retrieved 12 May 2012.
^ ^a ^b ^c ^d ^e Pool R (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): 486–492. doi:10.1097/00001573-200209000-00007. PMID 12357124.
^ Elangbam CS (October 2010). "Drug-induced valvulopathy: an update". Toxicologic Pathology. 38 (6): 837–848. CiteSeerX 10.1.1.1000.286. doi:10.1177/0192623310378027. PMID 20716786. S2CID 20796556.
^ ^a ^b Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL (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.
^ Astrup A (July 2010). "Drug management of obesity--efficacy versus safety". The New England Journal of Medicine. 363 (3): 288–290. doi:10.1056/NEJMe1004076. PMID 20647205.
^ ^a ^b Rothman RB, Baumann MH (April 2002). "Serotonin releasing agents. Neurochemical, therapeutic and adverse effects". Pharmacology, Biochemistry, and Behavior. 71 (4): 825–836. doi:10.1016/S0091-3057(01)00669-4. PMID 11888573. S2CID 24296122. Archived from the original on 2020-10-31. Retrieved 2019-08-02.
^ Miller KJ (October 2005). "Serotonin 5-ht2c receptor agonists: potential for the treatment of obesity". Molecular Interventions. 5 (5): 282–291. 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): 845–852. doi:10.1124/jpet.103.060806. PMID 14752059. S2CID 8056638.
^ ^a ^b ^c ^d ^e 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. Archived from the original on 2020-10-23. Retrieved 2024-05-27.
^ O'Donnell O, Ahuja G (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. S2CID 34370594.
^ Reynolds GP, Kirk SL (January 2010). "Metabolic side effects of antipsychotic drug treatment--pharmacological mechanisms". Pharmacology & Therapeutics. 125 (1): 169–179. doi:10.1016/j.pharmthera.2009.10.010. PMID 19931306.