Dexfenfluramine is believed to be solely responsible for theappetite suppressant properties of fenfluramine,[2] of which it has been demonstrated to mediate predominantly via activation ofpostsynaptic5-HT1B and5-HT2C receptors[6] through a combination of indirectserotonin releasing agent and directserotonin receptoragonist activities (the latter of which are mediated fully by itsactive metabolitedexnorfenfluramine).[7][8][9] Contrarily, levofenfluramine is thought to contribute only to unwantedside effects.[2] Paradoxically, however, it has been shown that levofenfluramine too acts as a relativelypotent releaser ofserotonin,[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 adopamine receptorantagonist,[12] which, as dopamine antagonists likeatypical antipsychotics are associated with causingincreased appetite andweight 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 potentnorepinephrine reuptake inhibitor (about 1/2 that of its efficacy as a serotonin releaser).[5][7][10] As such, it likely contributes significantly to thebiological 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 ofnorepinephrine,[10] and neither compound has any effect ondopamine reuptake or release.[10]
^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.PMID20647205.
^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.PMID16249524.
^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.PMID14752059.S2CID8056638.
^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.PMID9824670.S2CID34370594.
^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.PMID19931306.
