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 metabolitedexnorfenfluramine).[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]
^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.
^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.