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 postsynaptic5-HT1B and 5-HT2C receptors[6] through a combination of indirect serotonin releasing agent and direct serotonin receptoragonist 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 receptorantagonist,[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]
^ abRothman 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.
^James O'Donnell (Pharm. D.); Gopi Doctor Ahuja (30 May 2005). Drug Injury: Liability, Analysis, and Prevention. Lawyers & Judges Publishing Company. p. 306. ISBN978-0-913875-27-8. 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): 169–79. doi:10.1016/j.pharmthera.2009.10.010. PMID 19931306.
September 01, 2023
levofenfluramine, trifluoromethyl, ethylamphetamine, also, known, fenfluramine, fenfluramine, drug, amphetamine, family, that, itself, enantiopure, form, never, marketed, levorotatory, enantiomer, fenfluramine, racemic, form, compound, whereas, dextrorotatory,. 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 LevofenfluramineClinical dataATC codeNoneIdentifiersIUPAC name 2R N ethyl 1 3 trifluoromethyl phenyl 2 propanamineCAS Number37577 24 5 5220 89 3 HCl PubChem CID65801ChemSpider59217UNII953A94Y45BCompTox Dashboard EPA DTXSID60191009ECHA InfoCard100 164 235Chemical and physical dataFormulaC 12H 16F 3NMolar mass231 262 g mol 13D model JSmol Interactive imageSMILES FC F F c1cccc c1 C C H NCC CInChI 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 s1Key DBGIVFWFUFKIQN SECBINFHSA NDexfenfluramine 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 EditFenfluramine Dexfenfluramine NorfenfluramineReferences Edit 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 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 CiteSeerX 10 1 1 1000 286 doi 10 1177 0192623310378027 PMID 20716786 S2CID 20796556 a b 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 a b 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 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 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 59 doi 10 2174 156802606778249766 PMID 17017961 Archived from the original on 2012 03 03 James O Donnell Pharm D Gopi Doctor Ahuja 30 May 2005 Drug Injury Liability Analysis and Prevention Lawyers amp 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 amp Therapeutics 125 1 169 79 doi 10 1016 j pharmthera 2009 10 010 PMID 19931306 Retrieved from https en wikipedia org w index php title Levofenfluramine amp oldid 1121703029, wikipedia, wiki, book, books, library,
