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Michael H. Baumann - One of the best experts on this subject based on the ideXlab platform.
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fenfluramine and its major metabolite Norfenfluramine are potent substrates for norepinephrine transporters
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Richard B. Rothman, Robert D. Clark, John S. Partilla, Michael H. BaumannAbstract:(+/-)-Fenfluramine is an amphetamine analog that was once widely prescribed as an appetite suppressant. Although (+/-)-fenfluramine is no longer clinically available, the mechanisms underlying its anorectic properties are still of interest. Upon peripheral administration, stereoisomers of (+/-)-fenfluramine are N-deethylated to form the metabolites, (+)- and (-)-Norfenfluramine. It is well accepted that isomers of (+/-)-fenfluramine and (+/-)-Norfenfluramine interact with 5-hydroxytryptamine (serotonin, 5-HT) transporters to release 5-HT from neurons. However, the effects of these drugs on other monoamine transporters are not well characterized. In this study, we examined the interaction of stereoisomers of (+/-)-fenfluramine and (+/-)-Norfenfluramine with transporters for 5-HT, norepinephrine (NE), and dopamine (DA). Results from in vitro assays confirmed these drugs are potent substrates for 5-HT transporters: (+)-fenfluramine, (-)-fenfluramine, (+)-Norfenfluramine, and (-)-Norfenfluramine released [3H]5-HT from synaptosomes with EC50 values of 52, 147, 59, and 287 nM, respectively. Importantly, (+)-fenfluramine and (+)-Norfenfluramine released [3H]NE with EC50 values of 302 and 73 nM. Results from in vivo microdialysis experiments showed that intravenous injection of (+)-Norfenfluramine elevates extracellular levels of 5-HT, NE, and DA in rat frontal cortex. The effects of (+)-Norfenfluramine on NE and DA were antagonized by pretreatment with the NE uptake blocker nisoxetine. In summary, administration of fenfluramines can increase synaptic levels of 5-HT, NE, and DA in the cortex, and (+)-Norfenfluramine likely contributes to these effects. Release of NE and DA evoked by (+)-Norfenfluramine is at least partly mediated via NE transporters. Our results emphasize the potential involvement of noradrenergic mechanisms in the actions of fenfluramines.
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(+)-Fenfluramine and Its Major Metabolite, (+)-Norfenfluramine, Are Potent Substrates for Norepinephrine Transporters
The Journal of pharmacology and experimental therapeutics, 2003Co-Authors: Richard B. Rothman, Robert D. Clark, John S. Partilla, Michael H. BaumannAbstract:(+/-)-Fenfluramine is an amphetamine analog that was once widely prescribed as an appetite suppressant. Although (+/-)-fenfluramine is no longer clinically available, the mechanisms underlying its anorectic properties are still of interest. Upon peripheral administration, stereoisomers of (+/-)-fenfluramine are N-deethylated to form the metabolites, (+)- and (-)-Norfenfluramine. It is well accepted that isomers of (+/-)-fenfluramine and (+/-)-Norfenfluramine interact with 5-hydroxytryptamine (serotonin, 5-HT) transporters to release 5-HT from neurons. However, the effects of these drugs on other monoamine transporters are not well characterized. In this study, we examined the interaction of stereoisomers of (+/-)-fenfluramine and (+/-)-Norfenfluramine with transporters for 5-HT, norepinephrine (NE), and dopamine (DA). Results from in vitro assays confirmed these drugs are potent substrates for 5-HT transporters: (+)-fenfluramine, (-)-fenfluramine, (+)-Norfenfluramine, and (-)-Norfenfluramine released [3H]5-HT from synaptosomes with EC50 values of 52, 147, 59, and 287 nM, respectively. Importantly, (+)-fenfluramine and (+)-Norfenfluramine released [3H]NE with EC50 values of 302 and 73 nM. Results from in vivo microdialysis experiments showed that intravenous injection of (+)-Norfenfluramine elevates extracellular levels of 5-HT, NE, and DA in rat frontal cortex. The effects of (+)-Norfenfluramine on NE and DA were antagonized by pretreatment with the NE uptake blocker nisoxetine. In summary, administration of fenfluramines can increase synaptic levels of 5-HT, NE, and DA in the cortex, and (+)-Norfenfluramine likely contributes to these effects. Release of NE and DA evoked by (+)-Norfenfluramine is at least partly mediated via NE transporters. Our results emphasize the potential involvement of noradrenergic mechanisms in the actions of fenfluramines.
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Serotonin releasing agents: Neurochemical, therapeutic and adverse effects
Pharmacology Biochemistry and Behavior, 2002Co-Authors: Richard B. Rothman, Michael H. BaumannAbstract:Abstract This review summarizes the neurochemical, therapeutic and adverse effects of serotonin (5-HT) releasing agents. The 5-HT releaser (±)-fenfluramine is composed of two stereoisomers, (+)-fenfluramine and (−)-fenfluramine, which are N -de-ethylated to yield the metabolites, (+)-Norfenfluramine and (−)-Norfenfluramine. Fenfluramines and Norfenfluramines are 5-HT transporter substrates and potent 5-HT releasers. Other 5-HT releasing agents include m -chlorophenylpiperazine (mCPP), a major metabolite of the antidepressant drug trazodone. Findings from in vitro and in vivo studies support the hypothesis that fenfluramines and mCPP release neuronal 5-HT via a non-exocytotic carrier-mediated exchange mechanism involving 5-HT transporters. (+)-Norfenfluramine is a potent 5-HT 2B and 5-HT 2C receptor agonist. The former activity may increase the risk of developing valvular heart disease (VHD), whereas the latter activity is implicated in the anorectic effect of systemic fenfluramine. Anorectic agents that increase the risk of developing primary pulmonary hypertension (PPH) share the common property of being 5-HT transporter substrates. However, these drugs vary considerably in their propensity to increase the risk of PPH. In this regard, neither trazodone nor mCPP is associated with PPH. Similarly, although some 5-HT substrates can deplete brain 5-HT (fenfluramine), others do not (mCPP). In addition to the established indication of obesity, 5-HT releasers may be helpful in treating psychiatric problems such as drug and alcohol dependence, depression and premenstrual syndrome. Viewed collectively, it seems possible to develop new medications that selectively release 5-HT without the adverse effects of PPH, VHD or neurotoxicity. Such agents may have utility in treating a variety of psychiatric disorders.
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Therapeutic and adverse actions of serotonin transporter substrates.
Pharmacology & therapeutics, 2002Co-Authors: Richard B. Rothman, Michael H. BaumannAbstract:A variety of drugs release serotonin (5-HT, 5-hydroxytryptamine) from neurons by acting as substrates for 5-HT transporter (SERT) proteins. This review summarizes the neurochemical, therapeutic, and adverse actions of substrate-type 5-HT-releasing agents. The appetite suppressant (+/-)-fenfluramine is composed of (+) and (-) isomers, which are N-de-ethylated in the liver to yield the metabolites (+)- and (-)-Norfenfluramine. Fenfluramines and Norfenfluramines are potent 5-HT releasers. (+/-)-3,4-Methylenedioxymethamphetamine ((+/-)-MDMA, "ecstasy") and m-chlorophenylpiperazine (mCPP) are substrate-type 5-HT releasers. Fenfluramines, (+/-)-MDMA, and mCPP release neuronal 5-HT by a common non-exocytotic diffusion-exchange mechanism involving SERTs. (+)-Norfenfluramine is a potent 5-HT(2B) and 5-HT(2C) receptor agonist. The former activity may increase the risk of valvular heart disease, whereas the latter activity is implicated in the anorexic effect of systemic fenfluramine. Appetite suppressants that increase the risk for developing primary pulmonary hypertension (PPH) are all SERT substrates, but these drugs vary considerably in their propensity to increase this risk. For example, fenfluramine and aminorex are clearly linked to the occurrence of PPH, whereas other anorectics are not. Similarly, some SERT substrates deplete brain tissue 5-HT in animals (e.g., fenfluramine), while others do not (e.g., mCPP). In addition to the established indication of obesity, 5-HT releasers may help treat psychiatric disorders, such as drug and alcohol dependence, depression, and premenstrual syndrome. Viewed collectively, we believe new medications can be developed that selectively release 5-HT without increasing the risk for adverse effects of valvular heart disease, PPH, and neurotoxicity. Such agents may be useful for treating a variety of psychiatric disorders.
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Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications.
Circulation, 2000Co-Authors: Richard B. Rothman, Michael H. Baumann, Jason E. Savage, Laura Rauser, Ace Mcbride, Sandra J. Hufeisen, Bryan L. RothAbstract:Background—Serotonergic medications with various mechanisms of action are used to treat psychiatric disorders and are being investigated as treatments for drug dependence. The occurrence of fenfluramine-associated valvular heart disease (VHD) has raised concerns that other serotonergic medications might also increase the risk of developing VHD. We hypothesized that fenfluramine or its metabolite Norfenfluramine and other medications known to produce VHD have preferentially high affinities for a particular serotonin receptor subtype capable of stimulating mitogenesis. Methods and Results—Medications known or suspected to cause VHD (positive controls) and medications not associated with VHD (negative controls) were screened for activity at 11 cloned serotonin receptor subtypes by use of ligand-binding methods and functional assays. The positive control drugs were (±)-fenfluramine; (+)-fenfluramine; (−)-fenfluramine; its metabolites (±)-Norfenfluramine, (+)-Norfenfluramine, and (−)-Norfenfluramine; ergotamin...
Tiziana Mennini - One of the best experts on this subject based on the ideXlab platform.
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In vitro studies on the mechanism by which (+)-Norfenfluramine induces serotonin and dopamine release from the vesicular storage pool
Naunyn-Schmiedeberg's archives of pharmacology, 1998Co-Authors: Marco Gobbi, Alberto Parazzoli, Tiziana MenniniAbstract:(+)-Norfenfluramine is the main metabolite of the serotoninergic anorectic agent (+)-fenfluramine. Both compounds inhibit 5-HT reuptake and stimulate its release, although they induce release from different pools, with (+)-Norfenfluramine acting primarily on the cytoplasmic pool. Moreover, (+)-Norfenfluramine was more potent than the parent drug in inducing dopamine release. In order to investigate whether (+)-Norfenfluramine induces a Ca2+-dependent vesicular release, like some amphetamine derivatives, in the present study we preloaded synaptosomes with the [3H]neurotransmitter ([3H]5-HT or [3H]dopamine), superfused (washed) them for 47 min in the absence of pargyline and then exposed them to the releasing stimulus. With this protocol, the cytoplasmic pool should be absent and the [3H]neurotransmitter should mainly be stored in synaptic vesicles, where (+)-Norfenfluramine should act to induce release. This was confirmed by a significant decrease of (+)-Norfenfluramine-induced [3H]5-HT and [3H]dopamine release after reserpine pretreatment. The dose-response curves of (+)-Norfenfluramine-induced [3H]5-HT release were superimposable in hippocampus and hypothalamus, and also superimposable on the curve for (+)-fenfluramine-induced [3H]5-HT release; the dopamine releasing potency of (+)-Norfenfluramine in the striatum was more than ten times lower. The [3H]5-HT release induced by (+)-Norfenfluramine was partly (about 50%) but significantly Ca2+-dependent, and it was also markedly (68%) inhibited by Cd2+, a non-specific blocker of voltage-dependent Ca2+ channels, suggesting that the Ca2+-dependent release is mediated by entry of Ca2+ into the synaptosomes through these channels. The [3H]dopamine release induced by 5 µM (+)-Norfenfluramine was completely Ca2+-independent whereas at higher concentrations (10 and 20 µM) it was only slightly (20%) Ca2+-dependent. We have no clear explanation why (+)-Norfenfluramine has these different effects on serotoninergic and dopaminergic synaptosomes.
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in vitro studies on the mechanism by which Norfenfluramine induces serotonin and dopamine release from the vesicular storage pool
Naunyn-schmiedebergs Archives of Pharmacology, 1998Co-Authors: Marco Gobbi, Alberto Parazzoli, Tiziana MenniniAbstract:(+)-Norfenfluramine is the main metabolite of the serotoninergic anorectic agent (+)-fenfluramine. Both compounds inhibit 5-HT reuptake and stimulate its release, although they induce release from different pools, with (+)-Norfenfluramine acting primarily on the cytoplasmic pool. Moreover, (+)-Norfenfluramine was more potent than the parent drug in inducing dopamine release. In order to investigate whether (+)-Norfenfluramine induces a Ca2+-dependent vesicular release, like some amphetamine derivatives, in the present study we preloaded synaptosomes with the [3H]neurotransmitter ([3H]5-HT or [3H]dopamine), superfused (washed) them for 47 min in the absence of pargyline and then exposed them to the releasing stimulus. With this protocol, the cytoplasmic pool should be absent and the [3H]neurotransmitter should mainly be stored in synaptic vesicles, where (+)-Norfenfluramine should act to induce release. This was confirmed by a significant decrease of (+)-Norfenfluramine-induced [3H]5-HT and [3H]dopamine release after reserpine pretreatment. The dose-response curves of (+)-Norfenfluramine-induced [3H]5-HT release were superimposable in hippocampus and hypothalamus, and also superimposable on the curve for (+)-fenfluramine-induced [3H]5-HT release; the dopamine releasing potency of (+)-Norfenfluramine in the striatum was more than ten times lower. The [3H]5-HT release induced by (+)-Norfenfluramine was partly (about 50%) but significantly Ca2+-dependent, and it was also markedly (68%) inhibited by Cd2+, a non-specific blocker of voltage-dependent Ca2+ channels, suggesting that the Ca2+-dependent release is mediated by entry of Ca2+ into the synaptosomes through these channels. The [3H]dopamine release induced by 5 µM (+)-Norfenfluramine was completely Ca2+-independent whereas at higher concentrations (10 and 20 µM) it was only slightly (20%) Ca2+-dependent. We have no clear explanation why (+)-Norfenfluramine has these different effects on serotoninergic and dopaminergic synaptosomes.
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Comparative studies on the anorectic activity of d-fenfluramine in mice, rats, and guinea pigs
Naunyn-Schmiedeberg's Archives of Pharmacology, 1991Co-Authors: Tiziana Mennini, Adalgisa Bizzi, Silvio Caccia, Annamaria Codegoni, Claudia Fracasso, Emanuela Frittoli, Giovanna Guiso, Ines Martin Padura, Carlo Taddei, Angela UslenghiAbstract:The present study compares the anorectic activity of d -fenfluramine and its metabolite d -Norfenfluramine in three animal species. d -Fenfluramine and d -Norfenfluramine show anorectic activity at increasing doses (ED_50) in rats, guinea pigs, and mice, d -Norfenfluramine being more active than d -fenfluramine in all three species. Equiactive anorectic activities are reached with different brain levels of d -fenfluramine and d -Norfenfluramine, guinea pigs being the most sensitive species, followed by rats then mice. The metabolite most probably plays a major role in the anorectic effect of d -fenfluramine in guinea pigs, contributes to the anorectic activity in rats, but adds little to the action of the parent drug in mice. The different sensitivity to d -fenfluramine and d -Norfenfluramine in these three species does not appear to be explained by a number of biochemical parameters, including serotonin uptake or release, receptor subtypes, or ^3H- d -fenfluramine binding and uptake.
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Comparative studies on the anorectic activity of d-fenfluramine in mice, rats, and guinea pigs
Naunyn-Schmiedeberg's Archives of Pharmacology, 1991Co-Authors: Tiziana Mennini, Adalgisa Bizzi, Silvio Caccia, Annamaria Codegoni, Claudia Fracasso, Emanuela Frittoli, Giovanna Guiso, Ines Martin Padura, Carlo Taddei, Angela UslenghiAbstract:The present study compares the anorectic activity of d -fenfluramine and its metabolite d -Norfenfluramine in three animal species. d -Fenfluramine and d -Norfenfluramine show anorectic activity at increasing doses (ED_50) in rats, guinea pigs, and mice, d -Norfenfluramine being more active than d -fenfluramine in all three species. Equiactive anorectic activities are reached with different brain levels of d -fenfluramine and d -Norfenfluramine, guinea pigs being the most sensitive species, followed by rats then mice. The metabolite most probably plays a major role in the anorectic effect of d -fenfluramine in guinea pigs, contributes to the anorectic activity in rats, but adds little to the action of the parent drug in mice. The different sensitivity to d -fenfluramine and d -Norfenfluramine in these three species does not appear to be explained by a number of biochemical parameters, including serotonin uptake or release, receptor subtypes, or ^3H- d -fenfluramine binding and uptake.
Richard B. Rothman - One of the best experts on this subject based on the ideXlab platform.
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fenfluramine and its major metabolite Norfenfluramine are potent substrates for norepinephrine transporters
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Richard B. Rothman, Robert D. Clark, John S. Partilla, Michael H. BaumannAbstract:(+/-)-Fenfluramine is an amphetamine analog that was once widely prescribed as an appetite suppressant. Although (+/-)-fenfluramine is no longer clinically available, the mechanisms underlying its anorectic properties are still of interest. Upon peripheral administration, stereoisomers of (+/-)-fenfluramine are N-deethylated to form the metabolites, (+)- and (-)-Norfenfluramine. It is well accepted that isomers of (+/-)-fenfluramine and (+/-)-Norfenfluramine interact with 5-hydroxytryptamine (serotonin, 5-HT) transporters to release 5-HT from neurons. However, the effects of these drugs on other monoamine transporters are not well characterized. In this study, we examined the interaction of stereoisomers of (+/-)-fenfluramine and (+/-)-Norfenfluramine with transporters for 5-HT, norepinephrine (NE), and dopamine (DA). Results from in vitro assays confirmed these drugs are potent substrates for 5-HT transporters: (+)-fenfluramine, (-)-fenfluramine, (+)-Norfenfluramine, and (-)-Norfenfluramine released [3H]5-HT from synaptosomes with EC50 values of 52, 147, 59, and 287 nM, respectively. Importantly, (+)-fenfluramine and (+)-Norfenfluramine released [3H]NE with EC50 values of 302 and 73 nM. Results from in vivo microdialysis experiments showed that intravenous injection of (+)-Norfenfluramine elevates extracellular levels of 5-HT, NE, and DA in rat frontal cortex. The effects of (+)-Norfenfluramine on NE and DA were antagonized by pretreatment with the NE uptake blocker nisoxetine. In summary, administration of fenfluramines can increase synaptic levels of 5-HT, NE, and DA in the cortex, and (+)-Norfenfluramine likely contributes to these effects. Release of NE and DA evoked by (+)-Norfenfluramine is at least partly mediated via NE transporters. Our results emphasize the potential involvement of noradrenergic mechanisms in the actions of fenfluramines.
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3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) Induces Fenfluramine-Like Proliferative Actions on Human Cardiac Valvular Interstitial Cells in Vitro
Molecular pharmacology, 2003Co-Authors: Vincent Setola, Richard B. Rothman, Sandra J. Hufeisen, K. Jane Grande-allen, Ivan Vesely, Richard A. Glennon, Bruce E. Blough, Bryan L. RothAbstract:Recent findings have implicated the 5-hydroxytryptamine 2B (5-HT2B) serotonin receptor in mediating the heart valve fibroplasia [valvular heart disease (VHD)] and primary pulmonary hypertension observed in patients taking the now-banned appetite suppressant fenfluramine (Pondimin, Redux). Via large-scale, random screening of a portion of the receptorome, we have discovered that the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) and its N-demethylated metabolite 3,4-methylenedioxyamphetamine (MDA) each preferentially bind to and activate human recombinant 5-HT2B receptors. We also demonstrate that MDMA and MDA, like fenfluramine and its N-deethylated metabolite Norfenfluramine, elicit prolonged mitogenic responses in human valvular interstitial cells via activation of 5-HT2B receptors. We also report that pergolide and dihydroergotamine, two drugs recently demonstrated to induce VHD in humans, potently activate 5-HT2B receptors, thus validating this assay system for its ability to predict medications that might induce VHD. Our discovery that MDMA and a major metabolite, MDA, induce prolonged mitogenic responses in vitro similar to those induced by fenfluramine and Norfenfluramine in vivo (i.e., valvular interstitial cell fibroplasia) predict that long-term MDMA use could lead to the development of fenfluramine-like VHD. Because of the widespread abuse of MDMA, these findings have major public health implications. These findings also underscore the necessity of screening current and future drugs at h5-HT2B receptors for agonist actions before their use in humans.
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(+)-Fenfluramine and Its Major Metabolite, (+)-Norfenfluramine, Are Potent Substrates for Norepinephrine Transporters
The Journal of pharmacology and experimental therapeutics, 2003Co-Authors: Richard B. Rothman, Robert D. Clark, John S. Partilla, Michael H. BaumannAbstract:(+/-)-Fenfluramine is an amphetamine analog that was once widely prescribed as an appetite suppressant. Although (+/-)-fenfluramine is no longer clinically available, the mechanisms underlying its anorectic properties are still of interest. Upon peripheral administration, stereoisomers of (+/-)-fenfluramine are N-deethylated to form the metabolites, (+)- and (-)-Norfenfluramine. It is well accepted that isomers of (+/-)-fenfluramine and (+/-)-Norfenfluramine interact with 5-hydroxytryptamine (serotonin, 5-HT) transporters to release 5-HT from neurons. However, the effects of these drugs on other monoamine transporters are not well characterized. In this study, we examined the interaction of stereoisomers of (+/-)-fenfluramine and (+/-)-Norfenfluramine with transporters for 5-HT, norepinephrine (NE), and dopamine (DA). Results from in vitro assays confirmed these drugs are potent substrates for 5-HT transporters: (+)-fenfluramine, (-)-fenfluramine, (+)-Norfenfluramine, and (-)-Norfenfluramine released [3H]5-HT from synaptosomes with EC50 values of 52, 147, 59, and 287 nM, respectively. Importantly, (+)-fenfluramine and (+)-Norfenfluramine released [3H]NE with EC50 values of 302 and 73 nM. Results from in vivo microdialysis experiments showed that intravenous injection of (+)-Norfenfluramine elevates extracellular levels of 5-HT, NE, and DA in rat frontal cortex. The effects of (+)-Norfenfluramine on NE and DA were antagonized by pretreatment with the NE uptake blocker nisoxetine. In summary, administration of fenfluramines can increase synaptic levels of 5-HT, NE, and DA in the cortex, and (+)-Norfenfluramine likely contributes to these effects. Release of NE and DA evoked by (+)-Norfenfluramine is at least partly mediated via NE transporters. Our results emphasize the potential involvement of noradrenergic mechanisms in the actions of fenfluramines.
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Serotonin releasing agents: Neurochemical, therapeutic and adverse effects
Pharmacology Biochemistry and Behavior, 2002Co-Authors: Richard B. Rothman, Michael H. BaumannAbstract:Abstract This review summarizes the neurochemical, therapeutic and adverse effects of serotonin (5-HT) releasing agents. The 5-HT releaser (±)-fenfluramine is composed of two stereoisomers, (+)-fenfluramine and (−)-fenfluramine, which are N -de-ethylated to yield the metabolites, (+)-Norfenfluramine and (−)-Norfenfluramine. Fenfluramines and Norfenfluramines are 5-HT transporter substrates and potent 5-HT releasers. Other 5-HT releasing agents include m -chlorophenylpiperazine (mCPP), a major metabolite of the antidepressant drug trazodone. Findings from in vitro and in vivo studies support the hypothesis that fenfluramines and mCPP release neuronal 5-HT via a non-exocytotic carrier-mediated exchange mechanism involving 5-HT transporters. (+)-Norfenfluramine is a potent 5-HT 2B and 5-HT 2C receptor agonist. The former activity may increase the risk of developing valvular heart disease (VHD), whereas the latter activity is implicated in the anorectic effect of systemic fenfluramine. Anorectic agents that increase the risk of developing primary pulmonary hypertension (PPH) share the common property of being 5-HT transporter substrates. However, these drugs vary considerably in their propensity to increase the risk of PPH. In this regard, neither trazodone nor mCPP is associated with PPH. Similarly, although some 5-HT substrates can deplete brain 5-HT (fenfluramine), others do not (mCPP). In addition to the established indication of obesity, 5-HT releasers may be helpful in treating psychiatric problems such as drug and alcohol dependence, depression and premenstrual syndrome. Viewed collectively, it seems possible to develop new medications that selectively release 5-HT without the adverse effects of PPH, VHD or neurotoxicity. Such agents may have utility in treating a variety of psychiatric disorders.
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Therapeutic and adverse actions of serotonin transporter substrates.
Pharmacology & therapeutics, 2002Co-Authors: Richard B. Rothman, Michael H. BaumannAbstract:A variety of drugs release serotonin (5-HT, 5-hydroxytryptamine) from neurons by acting as substrates for 5-HT transporter (SERT) proteins. This review summarizes the neurochemical, therapeutic, and adverse actions of substrate-type 5-HT-releasing agents. The appetite suppressant (+/-)-fenfluramine is composed of (+) and (-) isomers, which are N-de-ethylated in the liver to yield the metabolites (+)- and (-)-Norfenfluramine. Fenfluramines and Norfenfluramines are potent 5-HT releasers. (+/-)-3,4-Methylenedioxymethamphetamine ((+/-)-MDMA, "ecstasy") and m-chlorophenylpiperazine (mCPP) are substrate-type 5-HT releasers. Fenfluramines, (+/-)-MDMA, and mCPP release neuronal 5-HT by a common non-exocytotic diffusion-exchange mechanism involving SERTs. (+)-Norfenfluramine is a potent 5-HT(2B) and 5-HT(2C) receptor agonist. The former activity may increase the risk of valvular heart disease, whereas the latter activity is implicated in the anorexic effect of systemic fenfluramine. Appetite suppressants that increase the risk for developing primary pulmonary hypertension (PPH) are all SERT substrates, but these drugs vary considerably in their propensity to increase this risk. For example, fenfluramine and aminorex are clearly linked to the occurrence of PPH, whereas other anorectics are not. Similarly, some SERT substrates deplete brain tissue 5-HT in animals (e.g., fenfluramine), while others do not (e.g., mCPP). In addition to the established indication of obesity, 5-HT releasers may help treat psychiatric disorders, such as drug and alcohol dependence, depression, and premenstrual syndrome. Viewed collectively, we believe new medications can be developed that selectively release 5-HT without increasing the risk for adverse effects of valvular heart disease, PPH, and neurotoxicity. Such agents may be useful for treating a variety of psychiatric disorders.
Stephanie W. Watts - One of the best experts on this subject based on the ideXlab platform.
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Norfenfluramine-induced arterial contraction is not dependent on endogenous 5-hydroxytryptamine or 5-hydroxytryptamine transporter. J Pharmacol Exp Ther
2016Co-Authors: Claudia S. Wilhelm, Michael Bader, Dennis L. Murphy, Keith Lookingl, Stephanie W. WattsAbstract:()-Norfenfluramine, the major metabolite of fenfluramine, causes vasoconstriction dependence on the 5-hydroxytrypta-mine (5-HT)2A receptor in rat. ()-Norfenfluramine was reported as a 5-hydroxytryptamine transporter (5-HTT) substrate and 5-HT releaser. Because the arterial 5-HTT exists and is func-tional in the rat, we hypothesized that ()-Norfenfluramine causes vasoconstriction by releasing 5-HT from vascular smooth muscle via 5-HTT. The released 5-HT, in turn, activates the 5-HT2A receptor. Isometric contractility experiments showed that ()-Norfenfluramine-induced mouse aortic con-traction was reduced by the 5-HTT inhibitor fluoxetine (1 M) but not by fluvoxamine (1 M). Tryptophan hydroxylase (TPH)-deficient (Tph1/) mice lack peripheral 5-HT. ()-Norfenflu-ramine (10 nM–100 M)-contracted aorta from wild-type an
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Corresponding Author:
2014Co-Authors: Claudia S. Wilhelm, Michael Bader, Dennis L. Murphy, Keith Lookingl, Stephanie W. WattsAbstract:(+)-Norfenfluramine-induced arterial contraction is not dependent on endogenous 5-HT or 5-HT
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the 5 hydroxytryptamine2a receptor is involved in Norfenfluramine induced arterial contraction and blood pressure increase in deoxycorticosterone acetate salt hypertension
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Gregory D. Fink, Stephanie W. WattsAbstract:The highly effective anorexigen (+)-fenfluramine was widely used to control body weight until the association with primary pulmonary hypertension and valvular heart disease. (+)-Norfenfluramine is the major hepatic metabolite of (+)-fenfluramine and is primarily responsible for the anorexic effect as well as side effects. We reported that (+)-Norfenfluramine causes vasoconstriction and a blood pressure increase in rats with normal blood pressure via the 5-hydroxytryptamine (5-HT)2A receptor. With the knowledge that (+)-Norfenfluramine also has affinity for 5-HT2B receptors and that arterial 5-HT2B receptor expression is up-regulated in deoxycorticosterone acetate (DOCA)-salt hypertension, we tested the hypothesis that (+)-Norfenfluramine-induced vasoconstriction and pressor effects are potentiated in DOCA-salt hypertensive rats in a 5-HT2 receptor-dependent manner. Contractions of arteries were measured using an isolated tissue bath system or myograph. Mean arterial blood pressure was measured in chronically instrumented conscious rats. Effects of (+)-Norfenfluramine in stimulating arterial contraction (leftward shift versus SHAM, aorta, 5.13-fold; renal artery, 1.95-fold; mesenteric resistance artery, 1.77-fold) and raising blood pressure were significantly enhanced in hypertension. In arteries from both normotensive and hypertensive rats, (+)-Norfenfluramine-induced contraction in aorta was inhibited by 5-HT2A receptor antagonists, ketanserin and LY53857 (4-isopropyl-7-methyl-9-(2-hydroxy-1-meth ylpropoxycarbonyl)4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline), but not by the 5-HT2B receptor antagonist, LY272015 [6-chloro-5-methyl-N-(5-quinolinyl)-2,3-dihydro-1H-indole-1-carboxamide]. Ketanserin (3 mg/kg) reduced (+)-Norfenfluramine-induced pressor response in both SHAM and DOCA rats. Our results demonstrate that (+)-Norfenfluramine-induced arterial contraction and blood pressure increases are potentiated in DOCA-salt hypertensive rats. However, it is the 5-HT2A receptor and not the 5-HT2B receptor that participates in these effects.
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The 5-Hydroxytryptamine2A Receptor Is Involved in (+)-Norfenfluramine-Induced Arterial Contraction and Blood Pressure Increase in Deoxycorticosterone Acetate-Salt Hypertension
The Journal of pharmacology and experimental therapeutics, 2007Co-Authors: Gregory D. Fink, Stephanie W. WattsAbstract:The highly effective anorexigen (+)-fenfluramine was widely used to control body weight until the association with primary pulmonary hypertension and valvular heart disease. (+)-Norfenfluramine is the major hepatic metabolite of (+)-fenfluramine and is primarily responsible for the anorexic effect as well as side effects. We reported that (+)-Norfenfluramine causes vasoconstriction and a blood pressure increase in rats with normal blood pressure via the 5-hydroxytryptamine (5-HT)2A receptor. With the knowledge that (+)-Norfenfluramine also has affinity for 5-HT2B receptors and that arterial 5-HT2B receptor expression is up-regulated in deoxycorticosterone acetate (DOCA)-salt hypertension, we tested the hypothesis that (+)-Norfenfluramine-induced vasoconstriction and pressor effects are potentiated in DOCA-salt hypertensive rats in a 5-HT2 receptor-dependent manner. Contractions of arteries were measured using an isolated tissue bath system or myograph. Mean arterial blood pressure was measured in chronically instrumented conscious rats. Effects of (+)-Norfenfluramine in stimulating arterial contraction (leftward shift versus SHAM, aorta, 5.13-fold; renal artery, 1.95-fold; mesenteric resistance artery, 1.77-fold) and raising blood pressure were significantly enhanced in hypertension. In arteries from both normotensive and hypertensive rats, (+)-Norfenfluramine-induced contraction in aorta was inhibited by 5-HT2A receptor antagonists, ketanserin and LY53857 (4-isopropyl-7-methyl-9-(2-hydroxy-1-meth ylpropoxycarbonyl)4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline), but not by the 5-HT2B receptor antagonist, LY272015 [6-chloro-5-methyl-N-(5-quinolinyl)-2,3-dihydro-1H-indole-1-carboxamide]. Ketanserin (3 mg/kg) reduced (+)-Norfenfluramine-induced pressor response in both SHAM and DOCA rats. Our results demonstrate that (+)-Norfenfluramine-induced arterial contraction and blood pressure increases are potentiated in DOCA-salt hypertensive rats. However, it is the 5-HT2A receptor and not the 5-HT2B receptor that participates in these effects.
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Norfenfluramine induced arterial contraction is not dependent on endogenous 5 hydroxytryptamine or 5 hydroxytryptamine transporter
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Claudia S. Wilhelm, Michael Bader, Dennis L. Murphy, Keith J. Lookingland, Stephanie W. WattsAbstract:(+)-Norfenfluramine, the major metabolite of fenfluramine, causes vasoconstriction dependence on the 5-hydroxytryptamine (5-HT)2A receptor in rat. (+)-Norfenfluramine was reported as a 5-hydroxytryptamine transporter (5-HTT) substrate and 5-HT releaser. Because the arterial 5-HTT exists and is functional in the rat, we hypothesized that (+)-Norfenfluramine causes vasoconstriction by releasing 5-HT from vascular smooth muscle via 5-HTT. The released 5-HT, in turn, activates the 5-HT2A receptor. Isometric contractility experiments showed that (+)-Norfenfluramine-induced mouse aortic contraction was reduced by the 5-HTT inhibitor fluoxetine (1 μM) but not by fluvoxamine (1 μM). Tryptophan hydroxylase (TPH)-deficient ( Tph1 – / –) mice lack peripheral 5-HT. (+)-Norfenfluramine (10 nM–100 μM)-contracted aorta from wild-type and Tph1 –/– mice with equivalent potency (–log EC50 [M], wild type = 5.73 ± 0.02, Tph1 –/– = 5.62 ± 0.09), and these contractions were inhibited by the 5-HT2A receptor antagonist ketanserin (3 nM) by a similar magnitude in aorta from wild-type and Tph1 –/– mice (wild type = 19.4, Tph1 –/– = 15.4-fold rightward shift versus control), as did fluoxetine (1 μM) (wild type = 22.4, Tph1 –/– = 28.8-fold rightward shift versus control). To further test the role of 5-HTT in (+)-Norfenfluramine-induced aortic contraction, the 5-HTT-targeted mutation mouse was used. (+)-Norfenfluramine induced similar aortic contraction in wild-type and 5-HTT-targeted mutation mice, and these contractions were inhibited by fluoxetine (1 μM). Thus, (+)-Norfenfluramine vasoconstriction is not dependent on 5-HTT-mediated release of endogenous 5-HT but by activating membrane 5-HT2A receptors directly. Understanding of the mechanism by which (+)-Norfenfluramine induces vasoconstriction is important to characterize and understand the function of the serotonergic system in peripheral arterial vasculature.
Marco Gobbi - One of the best experts on this subject based on the ideXlab platform.
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In vitro studies on the mechanism by which (+)-Norfenfluramine induces serotonin and dopamine release from the vesicular storage pool
Naunyn-Schmiedeberg's archives of pharmacology, 1998Co-Authors: Marco Gobbi, Alberto Parazzoli, Tiziana MenniniAbstract:(+)-Norfenfluramine is the main metabolite of the serotoninergic anorectic agent (+)-fenfluramine. Both compounds inhibit 5-HT reuptake and stimulate its release, although they induce release from different pools, with (+)-Norfenfluramine acting primarily on the cytoplasmic pool. Moreover, (+)-Norfenfluramine was more potent than the parent drug in inducing dopamine release. In order to investigate whether (+)-Norfenfluramine induces a Ca2+-dependent vesicular release, like some amphetamine derivatives, in the present study we preloaded synaptosomes with the [3H]neurotransmitter ([3H]5-HT or [3H]dopamine), superfused (washed) them for 47 min in the absence of pargyline and then exposed them to the releasing stimulus. With this protocol, the cytoplasmic pool should be absent and the [3H]neurotransmitter should mainly be stored in synaptic vesicles, where (+)-Norfenfluramine should act to induce release. This was confirmed by a significant decrease of (+)-Norfenfluramine-induced [3H]5-HT and [3H]dopamine release after reserpine pretreatment. The dose-response curves of (+)-Norfenfluramine-induced [3H]5-HT release were superimposable in hippocampus and hypothalamus, and also superimposable on the curve for (+)-fenfluramine-induced [3H]5-HT release; the dopamine releasing potency of (+)-Norfenfluramine in the striatum was more than ten times lower. The [3H]5-HT release induced by (+)-Norfenfluramine was partly (about 50%) but significantly Ca2+-dependent, and it was also markedly (68%) inhibited by Cd2+, a non-specific blocker of voltage-dependent Ca2+ channels, suggesting that the Ca2+-dependent release is mediated by entry of Ca2+ into the synaptosomes through these channels. The [3H]dopamine release induced by 5 µM (+)-Norfenfluramine was completely Ca2+-independent whereas at higher concentrations (10 and 20 µM) it was only slightly (20%) Ca2+-dependent. We have no clear explanation why (+)-Norfenfluramine has these different effects on serotoninergic and dopaminergic synaptosomes.
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in vitro studies on the mechanism by which Norfenfluramine induces serotonin and dopamine release from the vesicular storage pool
Naunyn-schmiedebergs Archives of Pharmacology, 1998Co-Authors: Marco Gobbi, Alberto Parazzoli, Tiziana MenniniAbstract:(+)-Norfenfluramine is the main metabolite of the serotoninergic anorectic agent (+)-fenfluramine. Both compounds inhibit 5-HT reuptake and stimulate its release, although they induce release from different pools, with (+)-Norfenfluramine acting primarily on the cytoplasmic pool. Moreover, (+)-Norfenfluramine was more potent than the parent drug in inducing dopamine release. In order to investigate whether (+)-Norfenfluramine induces a Ca2+-dependent vesicular release, like some amphetamine derivatives, in the present study we preloaded synaptosomes with the [3H]neurotransmitter ([3H]5-HT or [3H]dopamine), superfused (washed) them for 47 min in the absence of pargyline and then exposed them to the releasing stimulus. With this protocol, the cytoplasmic pool should be absent and the [3H]neurotransmitter should mainly be stored in synaptic vesicles, where (+)-Norfenfluramine should act to induce release. This was confirmed by a significant decrease of (+)-Norfenfluramine-induced [3H]5-HT and [3H]dopamine release after reserpine pretreatment. The dose-response curves of (+)-Norfenfluramine-induced [3H]5-HT release were superimposable in hippocampus and hypothalamus, and also superimposable on the curve for (+)-fenfluramine-induced [3H]5-HT release; the dopamine releasing potency of (+)-Norfenfluramine in the striatum was more than ten times lower. The [3H]5-HT release induced by (+)-Norfenfluramine was partly (about 50%) but significantly Ca2+-dependent, and it was also markedly (68%) inhibited by Cd2+, a non-specific blocker of voltage-dependent Ca2+ channels, suggesting that the Ca2+-dependent release is mediated by entry of Ca2+ into the synaptosomes through these channels. The [3H]dopamine release induced by 5 µM (+)-Norfenfluramine was completely Ca2+-independent whereas at higher concentrations (10 and 20 µM) it was only slightly (20%) Ca2+-dependent. We have no clear explanation why (+)-Norfenfluramine has these different effects on serotoninergic and dopaminergic synaptosomes.
