Discovery and characterization of potent small molecule inhibitors of the high affinity proline transporter
The mammalian proline transporter (PROT) is a high affinity Na +/Cl −-dependent transporter expressed in specific regions of the brain. It is homologous to other neurotransmitter transporters such as glycine, norepinephrine, serotonin, and dopamine transporters. PROT is enriched in glutamatergic syn...
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Veröffentlicht in: | Neuroscience letters 2009-02, Vol.451 (3), p.212-216 |
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creator | Yu, Xuan-Chuan Zhang, Wandong Oldham, Arian Buxton, Eric Patel, Shiv Nghi, Nguyen Tran, David Lanthorn, Thomas H. Bomont, Catherine Shi, Zhi-Cai Liu, Qingyun |
description | The mammalian proline transporter (PROT) is a high affinity Na
+/Cl
−-dependent transporter expressed in specific regions of the brain. It is homologous to other neurotransmitter transporters such as glycine, norepinephrine, serotonin, and dopamine transporters. PROT is enriched in glutamatergic synaptic terminals and may play an important role in the regulation of excitatory neurotransmission. No non-peptide small molecule inhibitors have been described for this transporter. To study its physiological role in the central nervous system and evaluate its potential as a therapeutic target, we established cell lines that stably express recombinant hPROT and characterized its kinetic properties for proline uptake. We then screened for inhibitors and identified a series of compounds that inhibit hPROT-mediated proline uptake. A known compound, benztropine, was found to inhibit hPROT with an IC
50 of 0.75
μM. A series of novel compounds were also found, one of which, LP-403812, showed an IC
50 of approximately 0.1
μM on both recombinant human and mouse PROT without significant inhibition of glycine and dopamine transporters at concentrations up to 10
μM. This compound also inhibited proline transporter activity of mouse brain synaptosomes with the same potency. These inhibitors provide important tools for the understanding of PROT functions in the brain and may lead to the development of therapeutic agents for certain neurological disorders. |
doi_str_mv | 10.1016/j.neulet.2009.01.018 |
format | Article |
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+/Cl
−-dependent transporter expressed in specific regions of the brain. It is homologous to other neurotransmitter transporters such as glycine, norepinephrine, serotonin, and dopamine transporters. PROT is enriched in glutamatergic synaptic terminals and may play an important role in the regulation of excitatory neurotransmission. No non-peptide small molecule inhibitors have been described for this transporter. To study its physiological role in the central nervous system and evaluate its potential as a therapeutic target, we established cell lines that stably express recombinant hPROT and characterized its kinetic properties for proline uptake. We then screened for inhibitors and identified a series of compounds that inhibit hPROT-mediated proline uptake. A known compound, benztropine, was found to inhibit hPROT with an IC
50 of 0.75
μM. A series of novel compounds were also found, one of which, LP-403812, showed an IC
50 of approximately 0.1
μM on both recombinant human and mouse PROT without significant inhibition of glycine and dopamine transporters at concentrations up to 10
μM. This compound also inhibited proline transporter activity of mouse brain synaptosomes with the same potency. These inhibitors provide important tools for the understanding of PROT functions in the brain and may lead to the development of therapeutic agents for certain neurological disorders.</description><identifier>ISSN: 0304-3940</identifier><identifier>EISSN: 1872-7972</identifier><identifier>DOI: 10.1016/j.neulet.2009.01.018</identifier><identifier>PMID: 19159658</identifier><identifier>CODEN: NELED5</identifier><language>eng</language><publisher>Shannon: Elsevier Ireland Ltd</publisher><subject>Amino Acid Transport Systems, Neutral - antagonists & inhibitors ; Amino Acid Transport Systems, Neutral - genetics ; Amino Acid Transport Systems, Neutral - metabolism ; Animals ; Base Sequence ; Benztropine - chemistry ; Benztropine - pharmacology ; Biological and medical sciences ; Brain - metabolism ; Brain - ultrastructure ; Cell Line ; Cercopithecus aethiops ; Cloning, Molecular ; COS Cells ; Dopamine transporter ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical - methods ; Enzyme Inhibitors - isolation & purification ; Enzyme Inhibitors - pharmacology ; Fundamental and applied biological sciences. Psychology ; Glycine transporter ; Humans ; Mice ; Molecular Structure ; Muscarinic Antagonists - pharmacology ; Presynaptic Terminals - metabolism ; Presynaptic Terminals - ultrastructure ; Proline transporter ; Proline transporter inhibitor ; Pyrazoles - pharmacology ; Recombinant Proteins - antagonists & inhibitors ; Recombinant Proteins - metabolism ; Synaptic Transmission - drug effects ; Synaptic Transmission - physiology ; Synaptosomes ; Thiazoles - pharmacology ; Transfection ; Vertebrates: nervous system and sense organs</subject><ispartof>Neuroscience letters, 2009-02, Vol.451 (3), p.212-216</ispartof><rights>2009 Elsevier Ireland Ltd</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-29897a85a36efdfe264f80f94ea2f77d2a780baaf2ac9b6dfbd54d08ed1136613</citedby><cites>FETCH-LOGICAL-c422t-29897a85a36efdfe264f80f94ea2f77d2a780baaf2ac9b6dfbd54d08ed1136613</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.neulet.2009.01.018$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21295393$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19159658$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yu, Xuan-Chuan</creatorcontrib><creatorcontrib>Zhang, Wandong</creatorcontrib><creatorcontrib>Oldham, Arian</creatorcontrib><creatorcontrib>Buxton, Eric</creatorcontrib><creatorcontrib>Patel, Shiv</creatorcontrib><creatorcontrib>Nghi, Nguyen</creatorcontrib><creatorcontrib>Tran, David</creatorcontrib><creatorcontrib>Lanthorn, Thomas H.</creatorcontrib><creatorcontrib>Bomont, Catherine</creatorcontrib><creatorcontrib>Shi, Zhi-Cai</creatorcontrib><creatorcontrib>Liu, Qingyun</creatorcontrib><title>Discovery and characterization of potent small molecule inhibitors of the high affinity proline transporter</title><title>Neuroscience letters</title><addtitle>Neurosci Lett</addtitle><description>The mammalian proline transporter (PROT) is a high affinity Na
+/Cl
−-dependent transporter expressed in specific regions of the brain. It is homologous to other neurotransmitter transporters such as glycine, norepinephrine, serotonin, and dopamine transporters. PROT is enriched in glutamatergic synaptic terminals and may play an important role in the regulation of excitatory neurotransmission. No non-peptide small molecule inhibitors have been described for this transporter. To study its physiological role in the central nervous system and evaluate its potential as a therapeutic target, we established cell lines that stably express recombinant hPROT and characterized its kinetic properties for proline uptake. We then screened for inhibitors and identified a series of compounds that inhibit hPROT-mediated proline uptake. A known compound, benztropine, was found to inhibit hPROT with an IC
50 of 0.75
μM. A series of novel compounds were also found, one of which, LP-403812, showed an IC
50 of approximately 0.1
μM on both recombinant human and mouse PROT without significant inhibition of glycine and dopamine transporters at concentrations up to 10
μM. This compound also inhibited proline transporter activity of mouse brain synaptosomes with the same potency. These inhibitors provide important tools for the understanding of PROT functions in the brain and may lead to the development of therapeutic agents for certain neurological disorders.</description><subject>Amino Acid Transport Systems, Neutral - antagonists & inhibitors</subject><subject>Amino Acid Transport Systems, Neutral - genetics</subject><subject>Amino Acid Transport Systems, Neutral - metabolism</subject><subject>Animals</subject><subject>Base Sequence</subject><subject>Benztropine - chemistry</subject><subject>Benztropine - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Brain - metabolism</subject><subject>Brain - ultrastructure</subject><subject>Cell Line</subject><subject>Cercopithecus aethiops</subject><subject>Cloning, Molecular</subject><subject>COS Cells</subject><subject>Dopamine transporter</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Evaluation, Preclinical - methods</subject><subject>Enzyme Inhibitors - isolation & purification</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Glycine transporter</subject><subject>Humans</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>Muscarinic Antagonists - pharmacology</subject><subject>Presynaptic Terminals - metabolism</subject><subject>Presynaptic Terminals - ultrastructure</subject><subject>Proline transporter</subject><subject>Proline transporter inhibitor</subject><subject>Pyrazoles - pharmacology</subject><subject>Recombinant Proteins - antagonists & inhibitors</subject><subject>Recombinant Proteins - metabolism</subject><subject>Synaptic Transmission - drug effects</subject><subject>Synaptic Transmission - physiology</subject><subject>Synaptosomes</subject><subject>Thiazoles - pharmacology</subject><subject>Transfection</subject><subject>Vertebrates: nervous system and sense organs</subject><issn>0304-3940</issn><issn>1872-7972</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU-LFDEQxYMo7rj6DURyUU89JunudHIRlvUvLHjRc0gnFTtjOhmTzML46c0wg94WCuryq1dV7yH0kpItJZS_220jHALULSNEbgltJR6hDRUT6yY5scdoQ3oydL0cyBV6VsqOEDLScXiKrqiko-Sj2KBfH3wx6R7yEetosVl01qZC9n909Sni5PA-VYgVl1WHgNcUwLS12MfFz76mXE5MXQAv_ueCtXM--nrE-5yCj4Br1rHsU26az9ETp0OBF5d-jX58-vj99kt39-3z19ubu84MjNWOSSEnLUbdc3DWAeODE8TJATRz02SZngSZtXZMGzlz62Y7DpYIsJT2nNP-Gr0967Ybfh-gVLW2JyEEHSEdihIjnzhlk2zkmwdJzoWUoh8aOJxBk1MpGZzaZ7_qfFSUqFMcaqfOcahTHIrQVqKNvbroH-YV7P-hi_8NeH0BdDE6uGaW8eUfxyiTYy_7xr0_c9B8u_eQVTEeogHrM5iqbPIPX_IXYLKtcg</recordid><startdate>20090227</startdate><enddate>20090227</enddate><creator>Yu, Xuan-Chuan</creator><creator>Zhang, Wandong</creator><creator>Oldham, Arian</creator><creator>Buxton, Eric</creator><creator>Patel, Shiv</creator><creator>Nghi, Nguyen</creator><creator>Tran, David</creator><creator>Lanthorn, Thomas H.</creator><creator>Bomont, Catherine</creator><creator>Shi, Zhi-Cai</creator><creator>Liu, Qingyun</creator><general>Elsevier Ireland Ltd</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7TK</scope></search><sort><creationdate>20090227</creationdate><title>Discovery and characterization of potent small molecule inhibitors of the high affinity proline transporter</title><author>Yu, Xuan-Chuan ; Zhang, Wandong ; Oldham, Arian ; Buxton, Eric ; Patel, Shiv ; Nghi, Nguyen ; Tran, David ; Lanthorn, Thomas H. ; Bomont, Catherine ; Shi, Zhi-Cai ; Liu, Qingyun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c422t-29897a85a36efdfe264f80f94ea2f77d2a780baaf2ac9b6dfbd54d08ed1136613</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Amino Acid Transport Systems, Neutral - antagonists & inhibitors</topic><topic>Amino Acid Transport Systems, Neutral - genetics</topic><topic>Amino Acid Transport Systems, Neutral - metabolism</topic><topic>Animals</topic><topic>Base Sequence</topic><topic>Benztropine - chemistry</topic><topic>Benztropine - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Brain - metabolism</topic><topic>Brain - ultrastructure</topic><topic>Cell Line</topic><topic>Cercopithecus aethiops</topic><topic>Cloning, Molecular</topic><topic>COS Cells</topic><topic>Dopamine transporter</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Evaluation, Preclinical - methods</topic><topic>Enzyme Inhibitors - isolation & purification</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Glycine transporter</topic><topic>Humans</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>Muscarinic Antagonists - pharmacology</topic><topic>Presynaptic Terminals - metabolism</topic><topic>Presynaptic Terminals - ultrastructure</topic><topic>Proline transporter</topic><topic>Proline transporter inhibitor</topic><topic>Pyrazoles - pharmacology</topic><topic>Recombinant Proteins - antagonists & inhibitors</topic><topic>Recombinant Proteins - metabolism</topic><topic>Synaptic Transmission - drug effects</topic><topic>Synaptic Transmission - physiology</topic><topic>Synaptosomes</topic><topic>Thiazoles - pharmacology</topic><topic>Transfection</topic><topic>Vertebrates: nervous system and sense organs</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yu, Xuan-Chuan</creatorcontrib><creatorcontrib>Zhang, Wandong</creatorcontrib><creatorcontrib>Oldham, Arian</creatorcontrib><creatorcontrib>Buxton, Eric</creatorcontrib><creatorcontrib>Patel, Shiv</creatorcontrib><creatorcontrib>Nghi, Nguyen</creatorcontrib><creatorcontrib>Tran, David</creatorcontrib><creatorcontrib>Lanthorn, Thomas H.</creatorcontrib><creatorcontrib>Bomont, Catherine</creatorcontrib><creatorcontrib>Shi, Zhi-Cai</creatorcontrib><creatorcontrib>Liu, Qingyun</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Neurosciences Abstracts</collection><jtitle>Neuroscience letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yu, Xuan-Chuan</au><au>Zhang, Wandong</au><au>Oldham, Arian</au><au>Buxton, Eric</au><au>Patel, Shiv</au><au>Nghi, Nguyen</au><au>Tran, David</au><au>Lanthorn, Thomas H.</au><au>Bomont, Catherine</au><au>Shi, Zhi-Cai</au><au>Liu, Qingyun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery and characterization of potent small molecule inhibitors of the high affinity proline transporter</atitle><jtitle>Neuroscience letters</jtitle><addtitle>Neurosci Lett</addtitle><date>2009-02-27</date><risdate>2009</risdate><volume>451</volume><issue>3</issue><spage>212</spage><epage>216</epage><pages>212-216</pages><issn>0304-3940</issn><eissn>1872-7972</eissn><coden>NELED5</coden><abstract>The mammalian proline transporter (PROT) is a high affinity Na
+/Cl
−-dependent transporter expressed in specific regions of the brain. It is homologous to other neurotransmitter transporters such as glycine, norepinephrine, serotonin, and dopamine transporters. PROT is enriched in glutamatergic synaptic terminals and may play an important role in the regulation of excitatory neurotransmission. No non-peptide small molecule inhibitors have been described for this transporter. To study its physiological role in the central nervous system and evaluate its potential as a therapeutic target, we established cell lines that stably express recombinant hPROT and characterized its kinetic properties for proline uptake. We then screened for inhibitors and identified a series of compounds that inhibit hPROT-mediated proline uptake. A known compound, benztropine, was found to inhibit hPROT with an IC
50 of 0.75
μM. A series of novel compounds were also found, one of which, LP-403812, showed an IC
50 of approximately 0.1
μM on both recombinant human and mouse PROT without significant inhibition of glycine and dopamine transporters at concentrations up to 10
μM. This compound also inhibited proline transporter activity of mouse brain synaptosomes with the same potency. These inhibitors provide important tools for the understanding of PROT functions in the brain and may lead to the development of therapeutic agents for certain neurological disorders.</abstract><cop>Shannon</cop><pub>Elsevier Ireland Ltd</pub><pmid>19159658</pmid><doi>10.1016/j.neulet.2009.01.018</doi><tpages>5</tpages></addata></record> |
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source | MEDLINE; Elsevier ScienceDirect Journals Complete |
subjects | Amino Acid Transport Systems, Neutral - antagonists & inhibitors Amino Acid Transport Systems, Neutral - genetics Amino Acid Transport Systems, Neutral - metabolism Animals Base Sequence Benztropine - chemistry Benztropine - pharmacology Biological and medical sciences Brain - metabolism Brain - ultrastructure Cell Line Cercopithecus aethiops Cloning, Molecular COS Cells Dopamine transporter Dose-Response Relationship, Drug Drug Evaluation, Preclinical - methods Enzyme Inhibitors - isolation & purification Enzyme Inhibitors - pharmacology Fundamental and applied biological sciences. Psychology Glycine transporter Humans Mice Molecular Structure Muscarinic Antagonists - pharmacology Presynaptic Terminals - metabolism Presynaptic Terminals - ultrastructure Proline transporter Proline transporter inhibitor Pyrazoles - pharmacology Recombinant Proteins - antagonists & inhibitors Recombinant Proteins - metabolism Synaptic Transmission - drug effects Synaptic Transmission - physiology Synaptosomes Thiazoles - pharmacology Transfection Vertebrates: nervous system and sense organs |
title | Discovery and characterization of potent small molecule inhibitors of the high affinity proline transporter |
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