Levofenfluramine
Non-marketed drug of the amphetamine class
From Wikipedia, the free encyclopedia
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.[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]
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| ECHA InfoCard | 100.164.235 |
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| Formula | C12H16F3N |
| Molar mass | 231.262 g·mol−1 |
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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-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]