5HT1A serotonin receptor agonists inhibit Plasmodium falciparum by blocking a membrane channel
Identifieur interne : 002154 ( Main/Exploration ); précédent : 002153; suivant : 0021555HT1A serotonin receptor agonists inhibit Plasmodium falciparum by blocking a membrane channel
Auteurs : Christopher P. Locher [États-Unis] ; Peter C. Ruben [États-Unis] ; Jiri Gut [États-Unis] ; Philip J. Rosenthal [États-Unis]Source :
- Antimicrobial agents and chemotherapy [ 0066-4804 ] ; 2003.
Descripteurs français
- KwdFr :
- 7-Dipropylamino-5,6,7,8-tétrahydro-1-naphtol (pharmacologie), Agonistes des récepteurs de la sérotonine (pharmacologie), Animaux, Antisérotonines (pharmacologie), Buspirone (pharmacologie), Canaux ioniques (), Fibroblastes, Humains, Ligands, Lignée cellulaire, Membrane cellulaire (), Plasmodium falciparum (), Plasmodium falciparum (croissance et développement), Potentiels de membrane (), Relation dose-effet des médicaments, Récepteur de la sérotonine de type 5-HT1A (), Survie cellulaire (), Techniques de patch-clamp.
- MESH :
- croissance et développement : Plasmodium falciparum.
- pharmacologie : 7-Dipropylamino-5,6,7,8-tétrahydro-1-naphtol, Agonistes des récepteurs de la sérotonine, Antisérotonines, Buspirone.
- Pascal (Inist)
- Animaux, Canaux ioniques, Fibroblastes, Humains, Ligands, Lignée cellulaire, Membrane cellulaire, Plasmodium falciparum, Potentiels de membrane, Relation dose-effet des médicaments, Récepteur de la sérotonine de type 5-HT1A, Récepteur sérotoninergique 5-HT1A, Agoniste, Plasmodium falciparum, Antipaludique, Antiparasitaire, In vitro, Mécanisme action, Canal membranaire, Canal ionique, Electrophysiologie, Survie cellulaire, Techniques de patch-clamp.
English descriptors
- KwdEn :
- 5-HT1A Serotonine receptor, 8-Hydroxy-2-(di-n-propylamino)tetralin (pharmacology), Agonist, Animals, Antimalarial, Buspirone (pharmacology), Cell Line, Cell Membrane (drug effects), Cell Survival (drug effects), Dose-Response Relationship, Drug, Electrophysiology, Fibroblasts, Humans, In vitro, Ion Channels (drug effects), Ionic channel, Ligands, Mechanism of action, Membrane Potentials (drug effects), Membrane channel, Parasiticide, Patch-Clamp Techniques, Plasmodium falciparum, Plasmodium falciparum (drug effects), Plasmodium falciparum (growth & development), Receptor, Serotonin, 5-HT1A (drug effects), Serotonin Antagonists (pharmacology), Serotonin Receptor Agonists (pharmacology).
- MESH :
- chemical , drug effects : Ion Channels, Receptor, Serotonin, 5-HT1A.
- chemical , pharmacology : 8-Hydroxy-2-(di-n-propylamino)tetralin, Buspirone, Serotonin Antagonists, Serotonin Receptor Agonists.
- drug effects : Cell Membrane, Cell Survival, Membrane Potentials, Plasmodium falciparum.
- growth & development : Plasmodium falciparum.
- Animals, Cell Line, Dose-Response Relationship, Drug, Fibroblasts, Humans, Ligands, Patch-Clamp Techniques.
Abstract
To identify new leads for the treatment of Plasmodium falciparum malaria, we screened a panel of serotonin (5-hydroxytryptamine [5HT]) receptor agonists and antagonists and determined their effects on parasite growth. The 5HT1A receptor agonists 8-hydroxy-N-(di-n-propyl)-aminotetralin (8-OH-DPAT), 2,5-dimethoxy-4-iodoamphetamine, and 2,5-dimethoxy-4-bromophenylethylamine inhibited the growth of P. falciparum in vitro (50% inhibitory concentrations, 0.4, 0.7, and 1.5 μM, respectively). In further characterizing the antiparasitic effects of 8-OH-DPAT, we found that this serotonin receptor agonist did not affect the growth of Leishmania infantum, Trypanosoma cruzi, Trypanosoma brucei brucei, or Trichostrongylus colubriformis in vitro and did not demonstrate cytotoxicity against the human lung fibroblast cell line MRC-5. 8-OH-DPAT had similar levels of growth inhibition against several different P. falciparum isolates having distinct chemotherapeutic resistance phenotypes, and its antimalarial effect was additive when it was used in combination with chloroquine against a chloroquine-resistant isolate. In a patch clamp assay, 8-OH-DPAT blocked a P. falciparum surface membrane channel, suggesting that serotonin receptor agonists are a novel class of antimalarials that target a nutrient transport pathway. Since there may be neurological involvement with the use of 8-OH-DPAT and other serotonin receptor agonists in the treatment of falciparum malaria, new lead compounds derived from 8-OH-DPAT will need to be modified to prevent potential neurological side effects. Nevertheless, these results suggest that 8-OH-DPAT is a new lead compound with which to derive novel antimalarial agents and is a useful tool with which to characterize P. falciparum membrane channels.
Affiliations:
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Le document en format XML
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Locher</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Tropical Medicine and Medical Microbiology, John A. Burns School of Medicine, University of Hawaii at Manoa</s1><s2>Honolulu, Hawaii 96816</s2><s3>USA</s3><sZ>1 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Honolulu, Hawaii 96816</wicri:noRegion></affiliation></author><author><name sortKey="Ruben, Peter C" sort="Ruben, Peter C" uniqKey="Ruben P" first="Peter C." last="Ruben">Peter C. Ruben</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Bekesy Laboratory, Pacific Biomedical Research Corporation</s1><s2>Honolulu, Hawaii 96822</s2><s3>USA</s3><sZ>2 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Honolulu, Hawaii 96822</wicri:noRegion></affiliation></author><author><name sortKey="Gut, Jiri" sort="Gut, Jiri" uniqKey="Gut J" first="Jiri" last="Gut">Jiri Gut</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Medicine, San Francisco General Hospital, University of California</s1><s2>San Francisco, California 94143-08113</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>San Francisco, California 94143-08113</wicri:noRegion></affiliation></author><author><name sortKey="Rosenthal, Philip J" sort="Rosenthal, Philip J" uniqKey="Rosenthal P" first="Philip J." last="Rosenthal">Philip J. Rosenthal</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Medicine, San Francisco General Hospital, University of California</s1><s2>San Francisco, California 94143-08113</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>San Francisco, California 94143-08113</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Antimicrobial agents and chemotherapy</title><title level="j" type="abbreviated">Antimicrob. agents chemother.</title><idno type="ISSN">0066-4804</idno><imprint><date when="2003">2003</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Antimicrobial agents and chemotherapy</title><title level="j" type="abbreviated">Antimicrob. agents chemother.</title><idno type="ISSN">0066-4804</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>5-HT1A Serotonine receptor</term><term>8-Hydroxy-2-(di-n-propylamino)tetralin (pharmacology)</term><term>Agonist</term><term>Animals</term><term>Antimalarial</term><term>Buspirone (pharmacology)</term><term>Cell Line</term><term>Cell Membrane (drug effects)</term><term>Cell Survival (drug effects)</term><term>Dose-Response Relationship, Drug</term><term>Electrophysiology</term><term>Fibroblasts</term><term>Humans</term><term>In vitro</term><term>Ion Channels (drug effects)</term><term>Ionic channel</term><term>Ligands</term><term>Mechanism of action</term><term>Membrane Potentials (drug effects)</term><term>Membrane channel</term><term>Parasiticide</term><term>Patch-Clamp Techniques</term><term>Plasmodium falciparum</term><term>Plasmodium falciparum (drug effects)</term><term>Plasmodium falciparum (growth & development)</term><term>Receptor, Serotonin, 5-HT1A (drug effects)</term><term>Serotonin Antagonists (pharmacology)</term><term>Serotonin Receptor Agonists (pharmacology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>7-Dipropylamino-5,6,7,8-tétrahydro-1-naphtol (pharmacologie)</term><term>Agonistes des récepteurs de la sérotonine (pharmacologie)</term><term>Animaux</term><term>Antisérotonines (pharmacologie)</term><term>Buspirone (pharmacologie)</term><term>Canaux ioniques ()</term><term>Fibroblastes</term><term>Humains</term><term>Ligands</term><term>Lignée cellulaire</term><term>Membrane cellulaire ()</term><term>Plasmodium falciparum ()</term><term>Plasmodium falciparum (croissance et développement)</term><term>Potentiels de membrane ()</term><term>Relation dose-effet des médicaments</term><term>Récepteur de la sérotonine de type 5-HT1A ()</term><term>Survie cellulaire ()</term><term>Techniques de patch-clamp</term></keywords><keywords scheme="MESH" type="chemical" qualifier="drug effects" xml:lang="en"><term>Ion Channels</term><term>Receptor, Serotonin, 5-HT1A</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>8-Hydroxy-2-(di-n-propylamino)tetralin</term><term>Buspirone</term><term>Serotonin Antagonists</term><term>Serotonin Receptor Agonists</term></keywords><keywords scheme="MESH" qualifier="croissance et développement" xml:lang="fr"><term>Plasmodium falciparum</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Membrane</term><term>Cell Survival</term><term>Membrane Potentials</term><term>Plasmodium falciparum</term></keywords><keywords scheme="MESH" qualifier="growth & development" xml:lang="en"><term>Plasmodium falciparum</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>7-Dipropylamino-5,6,7,8-tétrahydro-1-naphtol</term><term>Agonistes des récepteurs de la sérotonine</term><term>Antisérotonines</term><term>Buspirone</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line</term><term>Dose-Response Relationship, Drug</term><term>Fibroblasts</term><term>Humans</term><term>Ligands</term><term>Patch-Clamp Techniques</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Animaux</term><term>Canaux ioniques</term><term>Fibroblastes</term><term>Humains</term><term>Ligands</term><term>Lignée cellulaire</term><term>Membrane cellulaire</term><term>Plasmodium falciparum</term><term>Potentiels de membrane</term><term>Relation dose-effet des médicaments</term><term>Récepteur de la sérotonine de type 5-HT1A</term><term>Récepteur sérotoninergique 5-HT1A</term><term>Agoniste</term><term>Plasmodium falciparum</term><term>Antipaludique</term><term>Antiparasitaire</term><term>In vitro</term><term>Mécanisme action</term><term>Canal membranaire</term><term>Canal ionique</term><term>Electrophysiologie</term><term>Survie cellulaire</term><term>Techniques de patch-clamp</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">To identify new leads for the treatment of Plasmodium falciparum malaria, we screened a panel of serotonin (5-hydroxytryptamine [5HT]) receptor agonists and antagonists and determined their effects on parasite growth. The 5HT1A receptor agonists 8-hydroxy-N-(di-n-propyl)-aminotetralin (8-OH-DPAT), 2,5-dimethoxy-4-iodoamphetamine, and 2,5-dimethoxy-4-bromophenylethylamine inhibited the growth of P. falciparum in vitro (50% inhibitory concentrations, 0.4, 0.7, and 1.5 μM, respectively). In further characterizing the antiparasitic effects of 8-OH-DPAT, we found that this serotonin receptor agonist did not affect the growth of Leishmania infantum, Trypanosoma cruzi, Trypanosoma brucei brucei, or Trichostrongylus colubriformis in vitro and did not demonstrate cytotoxicity against the human lung fibroblast cell line MRC-5. 8-OH-DPAT had similar levels of growth inhibition against several different P. falciparum isolates having distinct chemotherapeutic resistance phenotypes, and its antimalarial effect was additive when it was used in combination with chloroquine against a chloroquine-resistant isolate. In a patch clamp assay, 8-OH-DPAT blocked a P. falciparum surface membrane channel, suggesting that serotonin receptor agonists are a novel class of antimalarials that target a nutrient transport pathway. Since there may be neurological involvement with the use of 8-OH-DPAT and other serotonin receptor agonists in the treatment of falciparum malaria, new lead compounds derived from 8-OH-DPAT will need to be modified to prevent potential neurological side effects. Nevertheless, these results suggest that 8-OH-DPAT is a new lead compound with which to derive novel antimalarial agents and is a useful tool with which to characterize P. falciparum membrane channels.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><country name="États-Unis"><noRegion><name sortKey="Locher, Christopher P" sort="Locher, Christopher P" uniqKey="Locher C" first="Christopher P." last="Locher">Christopher P. Locher</name></noRegion><name sortKey="Gut, Jiri" sort="Gut, Jiri" uniqKey="Gut J" first="Jiri" last="Gut">Jiri Gut</name><name sortKey="Rosenthal, Philip J" sort="Rosenthal, Philip J" uniqKey="Rosenthal P" first="Philip J." last="Rosenthal">Philip J. Rosenthal</name><name sortKey="Ruben, Peter C" sort="Ruben, Peter C" uniqKey="Ruben P" first="Peter C." last="Ruben">Peter C. Ruben</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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