levofenfluramine

{{Short description|Non-marketed drug of the amphetamine class}}

{{cs1 config|name-list-style=vanc}}

{{Drugbox

| IUPAC_name = (2R)-N-ethyl-1-[3-(trifluoromethyl)phenyl]-2-propanamine

| image = levofenfluramine.svg

| image_class = skin-invert-image

| image2 = Fenfluramine,levo 3D BS.png

| image_class2 = bg-transparent

| CAS_number = 37577-24-5

| CAS_supplemental =
5220-89-3 (HCl)

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 953A94Y45B

| ATC_prefix = None

| ATC_suffix =

| PubChem = 65801

| ChemSpiderID = 59217

| C=12 | H=16 | F=3 | N=1

| smiles = FC(F)(F)c1cccc(c1)C[C@H](NCC)C

| StdInChI = 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

| StdInChIKey = DBGIVFWFUFKIQN-SECBINFHSA-N

| bioavailability =

| protein_bound =

| metabolism =

| elimination_half-life =

| excretion =

| pregnancy_category =

| legal_status =

| routes_of_administration =

}}

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 alone.{{cite book |author=Chapman and Hall |url=https://books.google.com/books?id=x2Su3GKCvtsC&pg=PA3141 |title=Dictionary of Organic Compounds |publisher=CRC Press |year=1996 |isbn=978-0-412-54090-5 |page=3141 |access-date=12 May 2012}} It is the levorotatory enantiomer of fenfluramine, the racemic form of the compound, whereas the dextrorotatory enantiomer is dexfenfluramine.{{cite book | vauthors = Pool R |url=https://archive.org/details/fatfightingobesi00pool |title=Fat: Fighting the Obesity Epidemic |date=15 February 2001 |publisher=Oxford University Press |isbn=978-0-19-511853-7 |page=[https://archive.org/details/fatfightingobesi00pool/page/184 184] |access-date=12 May 2012 |url-access=registration}} 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,{{cite journal | vauthors = Seghatol FF, Rigolin VH | title = Appetite suppressants and valvular heart disease | journal = Current Opinion in Cardiology | volume = 17 | issue = 5 | pages = 486–492 | date = September 2002 | pmid = 12357124 | doi = 10.1097/00001573-200209000-00007 }} adverse effects that are likely to be caused by excessive stimulation of 5-HT_2B receptors expressed on heart valves.{{cite journal | vauthors = Elangbam CS | title = Drug-induced valvulopathy: an update | journal = Toxicologic Pathology | volume = 38 | issue = 6 | pages = 837–848 | date = October 2010 | pmid = 20716786 | doi = 10.1177/0192623310378027 | s2cid = 20796556 | citeseerx = 10.1.1.1000.286 }}{{cite journal | vauthors = Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL | title = Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications | journal = Circulation | volume = 102 | issue = 23 | pages = 2836–2841 | date = December 2000 | pmid = 11104741 | doi = 10.1161/01.CIR.102.23.2836 | doi-access = free }}

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-HT_1B and 5-HT_2C receptors{{cite journal | vauthors = Astrup A | title = Drug management of obesity--efficacy versus safety | journal = The New England Journal of Medicine | volume = 363 | issue = 3 | pages = 288–290 | date = July 2010 | pmid = 20647205 | doi = 10.1056/NEJMe1004076 }} 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).{{cite journal | vauthors = Rothman RB, Baumann MH | title = Serotonin releasing agents. Neurochemical, therapeutic and adverse effects | journal = Pharmacology, Biochemistry, and Behavior | volume = 71 | issue = 4 | pages = 825–836 | date = April 2002 | pmid = 11888573 | doi = 10.1016/S0091-3057(01)00669-4 | s2cid = 24296122 | url = https://zenodo.org/record/1259765 | access-date = 2019-08-02 | archive-date = 2020-10-31 | archive-url = https://web.archive.org/web/20201031081421/https://zenodo.org/record/1259765 | url-status = live }}{{cite journal | vauthors = Miller KJ | title = Serotonin 5-ht2c receptor agonists: potential for the treatment of obesity | journal = Molecular Interventions | volume = 5 | issue = 5 | pages = 282–291 | date = October 2005 | pmid = 16249524 | doi = 10.1124/mi.5.5.8 }}{{cite journal | vauthors = Ni W, Li MW, Thakali K, Fink GD, Watts SW | title = The fenfluramine metabolite (+)-norfenfluramine is vasoactive | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 309 | issue = 2 | pages = 845–852 | date = May 2004 | pmid = 14752059 | doi = 10.1124/jpet.103.060806 | s2cid = 8056638 }} 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,{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic potential of monoamine transporter substrates | journal = Current Topics in Medicinal Chemistry | volume = 6 | issue = 17 | pages = 1845–1859 | year = 2006 | pmid = 17017961 | doi = 10.2174/156802606778249766 | url = https://zenodo.org/record/1235860 | url-status = live | archive-url = https://web.archive.org/web/20201023101936/https://zenodo.org/record/1235860 | archive-date = 2020-10-23 | access-date = 2024-05-27 }} though with approximately 1/3 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.{{cite book | vauthors = O'Donnell O, Ahuja G | title = Drug Injury: Liability, Analysis, and Prevention | url = https://books.google.com/books?id=EB00rD8AqaYC&pg=PA306 | access-date = 12 May 2012 | date = 30 May 2005 | publisher = Lawyers & Judges Publishing Company | isbn = 978-0-913875-27-8 | page = 306}} 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,{{cite journal | vauthors = Balcioglu A, Wurtman RJ | title = Effects of fenfluramine and phentermine (fen-phen) on dopamine and serotonin release in rat striatum: in vivo microdialysis study in conscious animals | journal = Brain Research | volume = 813 | issue = 1 | pages = 67–72 | date = November 1998 | pmid = 9824670 | doi = 10.1016/S0006-8993(98)01003-8 | s2cid = 34370594 }} 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,{{cite journal | vauthors = Reynolds GP, Kirk SL | title = Metabolic side effects of antipsychotic drug treatment--pharmacological mechanisms | journal = Pharmacology & Therapeutics | volume = 125 | issue = 1 | pages = 169–179 | date = January 2010 | pmid = 19931306 | doi = 10.1016/j.pharmthera.2009.10.010 }} 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). 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, and neither compound has any effect on dopamine reuptake or release.