Arylbenzazepines are potent modulators for the delayed rectifier K+ channel: a potential mechanism for their neuroprotective effects
(+/-) SKF83959, like many other arylbenzazepines, elicits powerful neuroprotection in vitro and in vivo. The neuroprotective action of the compound was found to partially depend on its D(1)-like dopamine receptor agonistic activity. The precise mechanism for the (+/-) SKF83959-mediated neuroprotecti...
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| description | (+/-) SKF83959, like many other arylbenzazepines, elicits powerful neuroprotection in vitro and in vivo. The neuroprotective action of the compound was found to partially depend on its D(1)-like dopamine receptor agonistic activity. The precise mechanism for the (+/-) SKF83959-mediated neuroprotection remains elusive. We report here that (+/-) SKF83959 is a potent blocker for delayed rectifier K(+) channel. (+/-) SKF83959 inhibited the delayed rectifier K(+) current (I(K)) dose-dependently in rat hippocampal neurons. The IC(50) value for inhibition of I(K) was 41.9+/-2.3 microM (Hill coefficient = 1.81+/-0.13, n = 6), whereas that for inhibition of I(A) was 307.9+/-38.5 microM (Hill coefficient = 1.37+/-0.08, n = 6). Thus, (+/-) SKF83959 is 7.3-fold more potent in suppressing I(K) than I(A). Moreover, the inhibition of I(K) by (+/-) SKF83959 was voltage-dependent and not related to dopamine receptors. The rapidly onset of inhibition and recovery suggests that the inhibition resulted from a direct interaction of (+/-) SKF83959 with the K(+) channel. The intracellular application of (+/-) SKF83959 had no effects of on I(K), indicating that the compound most likely acts at the outer mouth of the pore of K(+) channel. We also tested the enantiomers of (+/-) SKF83959, R-(+) SKF83959 (MCL-201), and S-(-) SKF83959 (MCL-202), as well as SKF38393; all these compounds inhibited I(K). However, (+/-) SKF83959, at either 0.1 or 1 mM, exhibited the strongest inhibition on the currents among all tested drug. The present findings not only revealed a new potent blocker of I(K) , but also provided a novel mechanism for the neuroprotective action of arylbenzazepines such as (+/-) SKF83959. |
| doi_str_mv | 10.1371/journal.pone.0005811 |
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The neuroprotective action of the compound was found to partially depend on its D(1)-like dopamine receptor agonistic activity. The precise mechanism for the (+/-) SKF83959-mediated neuroprotection remains elusive. We report here that (+/-) SKF83959 is a potent blocker for delayed rectifier K(+) channel. (+/-) SKF83959 inhibited the delayed rectifier K(+) current (I(K)) dose-dependently in rat hippocampal neurons. The IC(50) value for inhibition of I(K) was 41.9+/-2.3 microM (Hill coefficient = 1.81+/-0.13, n = 6), whereas that for inhibition of I(A) was 307.9+/-38.5 microM (Hill coefficient = 1.37+/-0.08, n = 6). Thus, (+/-) SKF83959 is 7.3-fold more potent in suppressing I(K) than I(A). Moreover, the inhibition of I(K) by (+/-) SKF83959 was voltage-dependent and not related to dopamine receptors. The rapidly onset of inhibition and recovery suggests that the inhibition resulted from a direct interaction of (+/-) SKF83959 with the K(+) channel. The intracellular application of (+/-) SKF83959 had no effects of on I(K), indicating that the compound most likely acts at the outer mouth of the pore of K(+) channel. We also tested the enantiomers of (+/-) SKF83959, R-(+) SKF83959 (MCL-201), and S-(-) SKF83959 (MCL-202), as well as SKF38393; all these compounds inhibited I(K). However, (+/-) SKF83959, at either 0.1 or 1 mM, exhibited the strongest inhibition on the currents among all tested drug. The present findings not only revealed a new potent blocker of I(K) , but also provided a novel mechanism for the neuroprotective action of arylbenzazepines such as (+/-) SKF83959.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0005811</identifier><identifier>PMID: 19503734</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine - pharmacology ; Alcohol ; Animals ; Animals, Newborn ; Benzazepines - pharmacology ; Dopamine ; Dopamine Agonists - pharmacology ; Dopamine D1 receptors ; Drug abuse ; Enantiomers ; Hippocampus ; Hippocampus - metabolism ; Hypoxia ; Inhibition ; Inhibitory Concentration 50 ; Ischemia ; Laboratory animals ; Modulators ; Neurological Disorders/Movement Disorders ; Neurological Disorders/Neuropharmacology ; Neuromodulation ; Neurons - metabolism ; Neuroprotection ; Neuroprotective Agents - pharmacology ; Neurotoxicity ; Parkinson's disease ; Parkinsons disease ; Patch-Clamp Techniques ; Pharmaceutical sciences ; Pharmacology ; Pharmacology/Drug Development ; Potassium ; Potassium Channel Blockers - pharmacology ; Potassium channels ; Potassium channels (delayed-rectifying) ; Potassium Channels - metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors ; Receptors, Dopamine - metabolism ; Rodents</subject><ispartof>PloS one, 2009-06, Vol.4 (6), p.e5811</ispartof><rights>2009 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Chen et al. 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c524t-e72233d5f6d8c0345c51ce7ae4fe394547785fcbe6e45337408a3973f9bfb6393</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690691/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690691/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19503734$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Xue-Qin</creatorcontrib><creatorcontrib>Zhang, Jing</creatorcontrib><creatorcontrib>Neumeyer, John L</creatorcontrib><creatorcontrib>Jin, Guo-Zhang</creatorcontrib><creatorcontrib>Hu, Guo-Yuan</creatorcontrib><creatorcontrib>Zhang, Ao</creatorcontrib><creatorcontrib>Zhen, Xuechu</creatorcontrib><title>Arylbenzazepines are potent modulators for the delayed rectifier K+ channel: a potential mechanism for their neuroprotective effects</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>(+/-) SKF83959, like many other arylbenzazepines, elicits powerful neuroprotection in vitro and in vivo. The neuroprotective action of the compound was found to partially depend on its D(1)-like dopamine receptor agonistic activity. The precise mechanism for the (+/-) SKF83959-mediated neuroprotection remains elusive. We report here that (+/-) SKF83959 is a potent blocker for delayed rectifier K(+) channel. (+/-) SKF83959 inhibited the delayed rectifier K(+) current (I(K)) dose-dependently in rat hippocampal neurons. The IC(50) value for inhibition of I(K) was 41.9+/-2.3 microM (Hill coefficient = 1.81+/-0.13, n = 6), whereas that for inhibition of I(A) was 307.9+/-38.5 microM (Hill coefficient = 1.37+/-0.08, n = 6). Thus, (+/-) SKF83959 is 7.3-fold more potent in suppressing I(K) than I(A). Moreover, the inhibition of I(K) by (+/-) SKF83959 was voltage-dependent and not related to dopamine receptors. The rapidly onset of inhibition and recovery suggests that the inhibition resulted from a direct interaction of (+/-) SKF83959 with the K(+) channel. The intracellular application of (+/-) SKF83959 had no effects of on I(K), indicating that the compound most likely acts at the outer mouth of the pore of K(+) channel. We also tested the enantiomers of (+/-) SKF83959, R-(+) SKF83959 (MCL-201), and S-(-) SKF83959 (MCL-202), as well as SKF38393; all these compounds inhibited I(K). However, (+/-) SKF83959, at either 0.1 or 1 mM, exhibited the strongest inhibition on the currents among all tested drug. The present findings not only revealed a new potent blocker of I(K) , but also provided a novel mechanism for the neuroprotective action of arylbenzazepines such as (+/-) SKF83959.</description><subject>2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine - pharmacology</subject><subject>Alcohol</subject><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Benzazepines - pharmacology</subject><subject>Dopamine</subject><subject>Dopamine Agonists - pharmacology</subject><subject>Dopamine D1 receptors</subject><subject>Drug abuse</subject><subject>Enantiomers</subject><subject>Hippocampus</subject><subject>Hippocampus - metabolism</subject><subject>Hypoxia</subject><subject>Inhibition</subject><subject>Inhibitory Concentration 50</subject><subject>Ischemia</subject><subject>Laboratory animals</subject><subject>Modulators</subject><subject>Neurological Disorders/Movement Disorders</subject><subject>Neurological Disorders/Neuropharmacology</subject><subject>Neuromodulation</subject><subject>Neurons - metabolism</subject><subject>Neuroprotection</subject><subject>Neuroprotective Agents - pharmacology</subject><subject>Neurotoxicity</subject><subject>Parkinson's disease</subject><subject>Parkinsons disease</subject><subject>Patch-Clamp Techniques</subject><subject>Pharmaceutical sciences</subject><subject>Pharmacology</subject><subject>Pharmacology/Drug Development</subject><subject>Potassium</subject><subject>Potassium Channel Blockers - pharmacology</subject><subject>Potassium channels</subject><subject>Potassium channels (delayed-rectifying)</subject><subject>Potassium Channels - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors</subject><subject>Receptors, Dopamine - metabolism</subject><subject>Rodents</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNp1kkFv1DAQhS0Eou3CP0BgiSPaxY7t2OaAVFUUKipxgbPlOOOuV04c7KTS9swPJ8um0B44eTR-35vR6CH0ipINZZK-36Up9zZuhtTDhhAiFKVP0CnVrFrXFWFPH9Qn6KyU3axhqq6foxOqBWGS8VP06zzvYwP9nb2DIfRQsM2AhzRCP-IutVO0Y8oF-5TxuAXcQrR7aHEGNwYfIOOv77Db2r6H-AHbhQw24g4O7VC6ezZk3MOU05BnzUzfAgbv56q8QM-8jQVeLu8K_bj89P3iy_r62-eri_PrtRMVH9cgq4qxVvi6VY4wLpygDqQF7oFpLriUSnjXQA1cMCY5UZZpybxufFMzzVbozdF3iKmY5YDF0Erpimg-Qyt0dVS0ye7MkENn894kG8yfRso3xuYxuAhGCqJarSprCee6YQ1vlFVUQtsIaamavT4u06amg9bNd8k2PjJ9_NOHrblJt6aqNak1nQ3eLgY5_ZygjP9ZmR9VLqdSMvi_Eygxh6TcU-aQFLMkZcZeP9zuH7REg_0GdAi_aA</recordid><startdate>20090605</startdate><enddate>20090605</enddate><creator>Chen, Xue-Qin</creator><creator>Zhang, Jing</creator><creator>Neumeyer, John L</creator><creator>Jin, Guo-Zhang</creator><creator>Hu, Guo-Yuan</creator><creator>Zhang, Ao</creator><creator>Zhen, Xuechu</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20090605</creationdate><title>Arylbenzazepines are potent modulators for the delayed rectifier K+ channel: a potential mechanism for their neuroprotective effects</title><author>Chen, Xue-Qin ; Zhang, Jing ; Neumeyer, John L ; Jin, Guo-Zhang ; Hu, Guo-Yuan ; Zhang, Ao ; Zhen, Xuechu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c524t-e72233d5f6d8c0345c51ce7ae4fe394547785fcbe6e45337408a3973f9bfb6393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine - pharmacology</topic><topic>Alcohol</topic><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Benzazepines - pharmacology</topic><topic>Dopamine</topic><topic>Dopamine Agonists - pharmacology</topic><topic>Dopamine D1 receptors</topic><topic>Drug abuse</topic><topic>Enantiomers</topic><topic>Hippocampus</topic><topic>Hippocampus - metabolism</topic><topic>Hypoxia</topic><topic>Inhibition</topic><topic>Inhibitory Concentration 50</topic><topic>Ischemia</topic><topic>Laboratory animals</topic><topic>Modulators</topic><topic>Neurological Disorders/Movement Disorders</topic><topic>Neurological Disorders/Neuropharmacology</topic><topic>Neuromodulation</topic><topic>Neurons - metabolism</topic><topic>Neuroprotection</topic><topic>Neuroprotective Agents - pharmacology</topic><topic>Neurotoxicity</topic><topic>Parkinson's disease</topic><topic>Parkinsons disease</topic><topic>Patch-Clamp Techniques</topic><topic>Pharmaceutical sciences</topic><topic>Pharmacology</topic><topic>Pharmacology/Drug Development</topic><topic>Potassium</topic><topic>Potassium Channel Blockers - 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The neuroprotective action of the compound was found to partially depend on its D(1)-like dopamine receptor agonistic activity. The precise mechanism for the (+/-) SKF83959-mediated neuroprotection remains elusive. We report here that (+/-) SKF83959 is a potent blocker for delayed rectifier K(+) channel. (+/-) SKF83959 inhibited the delayed rectifier K(+) current (I(K)) dose-dependently in rat hippocampal neurons. The IC(50) value for inhibition of I(K) was 41.9+/-2.3 microM (Hill coefficient = 1.81+/-0.13, n = 6), whereas that for inhibition of I(A) was 307.9+/-38.5 microM (Hill coefficient = 1.37+/-0.08, n = 6). Thus, (+/-) SKF83959 is 7.3-fold more potent in suppressing I(K) than I(A). Moreover, the inhibition of I(K) by (+/-) SKF83959 was voltage-dependent and not related to dopamine receptors. The rapidly onset of inhibition and recovery suggests that the inhibition resulted from a direct interaction of (+/-) SKF83959 with the K(+) channel. The intracellular application of (+/-) SKF83959 had no effects of on I(K), indicating that the compound most likely acts at the outer mouth of the pore of K(+) channel. We also tested the enantiomers of (+/-) SKF83959, R-(+) SKF83959 (MCL-201), and S-(-) SKF83959 (MCL-202), as well as SKF38393; all these compounds inhibited I(K). However, (+/-) SKF83959, at either 0.1 or 1 mM, exhibited the strongest inhibition on the currents among all tested drug. The present findings not only revealed a new potent blocker of I(K) , but also provided a novel mechanism for the neuroprotective action of arylbenzazepines such as (+/-) SKF83959.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>19503734</pmid><doi>10.1371/journal.pone.0005811</doi><oa>free_for_read</oa></addata></record> |
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| subjects | 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine - pharmacology Alcohol Animals Animals, Newborn Benzazepines - pharmacology Dopamine Dopamine Agonists - pharmacology Dopamine D1 receptors Drug abuse Enantiomers Hippocampus Hippocampus - metabolism Hypoxia Inhibition Inhibitory Concentration 50 Ischemia Laboratory animals Modulators Neurological Disorders/Movement Disorders Neurological Disorders/Neuropharmacology Neuromodulation Neurons - metabolism Neuroprotection Neuroprotective Agents - pharmacology Neurotoxicity Parkinson's disease Parkinsons disease Patch-Clamp Techniques Pharmaceutical sciences Pharmacology Pharmacology/Drug Development Potassium Potassium Channel Blockers - pharmacology Potassium channels Potassium channels (delayed-rectifying) Potassium Channels - metabolism Rats Rats, Sprague-Dawley Receptors Receptors, Dopamine - metabolism Rodents |
| title | Arylbenzazepines are potent modulators for the delayed rectifier K+ channel: a potential mechanism for their neuroprotective effects |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-04T20%3A48%3A26IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Arylbenzazepines%20are%20potent%20modulators%20for%20the%20delayed%20rectifier%20K+%20channel:%20a%20potential%20mechanism%20for%20their%20neuroprotective%20effects&rft.jtitle=PloS%20one&rft.au=Chen,%20Xue-Qin&rft.date=2009-06-05&rft.volume=4&rft.issue=6&rft.spage=e5811&rft.pages=e5811-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0005811&rft_dat=%3Cproquest_plos_%3E2896798301%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1289209445&rft_id=info:pmid/19503734&rft_doaj_id=oai_doaj_org_article_7508d982aa0449b3b4b8a817edb57a18&rfr_iscdi=true |