Aminorex, Fenfluramine, and Chlorphentermine Are Serotonin Transporter Substrates

Rothman, Richard B.; Ayestas, Mario A.; Dersch, Christina M.; Baumann, Michael H.

doi:10.1161/01.cir.100.8.869

Cited by 194 publications

(143 citation statements)

References 32 publications

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“…SERTs play a major role in this process by allowing drugs to accumulate to high concentrations within cells. The validity of this hypothesis and its relevance to other adverse effects of FEN and dFEN in non-neural tissues (i.e., cardiac valvulopathy and pulmonary hypertension) remains to be determined (Rothman et al 1999).…”

Section: Discussionmentioning

confidence: 99%

1-(m-Chlorophenyl)piperazine (mCPP) Dissociates In Vivo Serotonin Release from Long-Term Serotonin Depletion in Rat Brain

Baumann

Ayestas

Dersch

et al. 2001

Neuropsychopharmacology

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Section: Discussionmentioning

confidence: 99%

1-(m-Chlorophenyl)piperazine (mCPP) Dissociates In Vivo Serotonin Release from Long-Term Serotonin Depletion in Rat Brain

Baumann

Ayestas

Dersch

et al. 2001

Neuropsychopharmacology

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“…The profile of 5HT release caused by phentermine does not resemble that of a 5HT uptake inhibitor which, regardless of potency, would take much longer (1 -1.5 h 5,6 ) to maximally increase extracellular 5HT. In any event, phentermine has already been shown to be essentially inactive as a 5HT uptake inhibitor in vitro 14,17 (IC 50 ¼ 11 -14 mM). As for alternative mechanisms, although inhibition of monoamine oxidase (MAO) can yield relatively rapid elevations of extracellular 5HT, 18 these are usually persistent and can continue to rise for up to 5 h. 18,19 Again, however, phentermine has been shown to be extremely weak as an inhibitor of MAO A (IC 50 ¼ 100 -200 mM) 20,21 or MAO B (IC 50 ¼ 300 -900 mM).…”

Section: Discussionmentioning

confidence: 99%

Additive effects on rat brain 5HT release of combining phentermine with dexfenfluramine

et al. 2001

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OBJECTIVE AND DESIGN:This study examined the effects of the anti-obesity agents, phentermine and dexfenfluramine given alone or in combination, on in vitro and in vivo 5HT release from rat brain tissue. RESULTS: In vitro, phentermine was without effect on basal [ 3 H]5HT efflux from hypothalamic slices whereas dexfenfluramine (10 mM) evoked a 131% increase in [ 3 H]5HT release. In combination, the two drugs did not alter [ 3 H]5HT release beyond that caused by dexfenfluramine alone. At pharmacologically equivalent doses, phentermine (5.7 mg=kg, i.p.) caused a rapid, modest elevation, and dexfenfluramine (3 mg=kg, i.p.) a larger but equally rapid elevation of extracellular 5HT in the microdialysates from the rat anterior hypothalamus. In combination, the increase in extracellular 5HT evoked by these drugs was not significantly greater than the sum of their individual effects. CONCLUSIONS: This study provides evidence that phentermine's actions are not restricted to catecholamine systems and indicates that combining phentermine with dexfenfluramine results in an additive increase in neuronal 5HT release.

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“…These medications were removed from clinical use in 1997 due to the occurrence of CVD in some patients [67]. We reported that fenfluramine, aminorex, and other amphetaminerelated drugs known to increase the risk for developing PPH (e.g., chlorphentermine) share the common feature of being SERT substrates [68]. Our findings implicated SERT in the mechanism underlying fenfluramine-induced PPH.…”

Section: Adverse Effectsmentioning

confidence: 66%

Therapeutic Potential of Monoamine Transporter Substrates

Rothman¹,

Baumann²

2006

CTMC

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Monoamine transporter proteins are targets for many psychoactive compounds, including therapeutic and abused stimulant drugs. This paper reviews recent work from our laboratory investigating the interaction of stimulants with transporters in brain tissue. We illustrate how determining the precise mechanism of stimulant drug action (uptake inhibitor vs. substrate) can provide unique opportunities for medication discovery. An important lesson learned from this work is that drugs which display equipotent substrate activity at dopamine (DA) and serotonin (5-HT) transporters have minimal abuse liability and few stimulant side-effects, yet are able to suppress ongoing drug-seeking behavior. As a specific example, we describe the development of PAL-287 (α-methylnapthylethylamine), a dual DA/5-HT releasing agent that suppresses cocaine self-administration in rhesus monkeys, without the adverse effects associated with older phenylethylamine 5-HT releasers (e.g., fenfluramine) and DA releasers (e.g., amphetamine). Our findings demonstrate the feasibility of developing non-amphetamine releasing agents as potential treatments for substance abuse disorders and other psychiatric conditions.

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Aminorex, Fenfluramine, and Chlorphentermine Are Serotonin Transporter Substrates

Cited by 194 publications

References 32 publications

1-(m-Chlorophenyl)piperazine (mCPP) Dissociates In Vivo Serotonin Release from Long-Term Serotonin Depletion in Rat Brain

1-(m-Chlorophenyl)piperazine (mCPP) Dissociates In Vivo Serotonin Release from Long-Term Serotonin Depletion in Rat Brain

Additive effects on rat brain 5HT release of combining phentermine with dexfenfluramine

Therapeutic Potential of Monoamine Transporter Substrates

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