PSAB-OFP, a selective alpha 7 nicotinic receptor agonist, is also a potent agonist of the 5-HT3 receptor
5-Hydroxytryptamine 3 (5-HT(3)) and alpha 7 nicotinic receptors share high sequence homology and pharmacological cross-reactivity. An assessment of the potential role of alpha 7 receptors in many neurophysiological processes, and hence their therapeutic value, requires the development of selective a...
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| Veröffentlicht in: | European journal of pharmacology 2002-10, Vol.452 (2), p.137-144 |
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| container_title | European journal of pharmacology |
| container_volume | 452 |
| creator | Broad, Lisa M Felthouse, Catherine Zwart, Ruud McPhie, Gordon I Pearson, Kathy H Craig, Peter J Wallace, Louise Broadmore, Richard J Boot, John R Keenan, Martine Baker, S Richard Sher, Emanuele |
| description | 5-Hydroxytryptamine 3 (5-HT(3)) and alpha 7 nicotinic receptors share high sequence homology and pharmacological cross-reactivity. An assessment of the potential role of alpha 7 receptors in many neurophysiological processes, and hence their therapeutic value, requires the development of selective alpha 7 receptor agonists. We used a recently reported selective alpha 7 receptor agonist, (R)-(-)-5'Phenylspiro[1-azabicyclo[2.2.2] octane-3,2'-(3'H)furo[2,3-b]pyridine (PSAB-OFP) and confirmed its activity on human recombinant alpha 7 receptors. However, PSAB-OFP also displayed high affinity binding to 5-HT(3) receptors. To assess the functional activity of PSAB-OFP on 5-HT(3) receptors we studied recombinant human 5-HT(3) receptors expressed in Xenopus oocytes, as well as native mouse 5-HT(3) receptors expressed in N1E-115 neuroblastoma cells, using whole-cell patch clamp and Ca(2+) imaging. Our results show that PSAB-OFP is an equipotent, partial agonist of both alpha 7 and 5-HT(3) receptors. We conclude that it will be necessary to identify the determinant of this overlapping pharmacology in order to develop more selective alpha 7 receptor ligands. |
| doi_str_mv | 10.1016/S0014-2999(02)02273-2 |
| format | Article |
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An assessment of the potential role of alpha 7 receptors in many neurophysiological processes, and hence their therapeutic value, requires the development of selective alpha 7 receptor agonists. We used a recently reported selective alpha 7 receptor agonist, (R)-(-)-5'Phenylspiro[1-azabicyclo[2.2.2] octane-3,2'-(3'H)furo[2,3-b]pyridine (PSAB-OFP) and confirmed its activity on human recombinant alpha 7 receptors. However, PSAB-OFP also displayed high affinity binding to 5-HT(3) receptors. To assess the functional activity of PSAB-OFP on 5-HT(3) receptors we studied recombinant human 5-HT(3) receptors expressed in Xenopus oocytes, as well as native mouse 5-HT(3) receptors expressed in N1E-115 neuroblastoma cells, using whole-cell patch clamp and Ca(2+) imaging. Our results show that PSAB-OFP is an equipotent, partial agonist of both alpha 7 and 5-HT(3) receptors. We conclude that it will be necessary to identify the determinant of this overlapping pharmacology in order to develop more selective alpha 7 receptor ligands.</description><identifier>ISSN: 0014-2999</identifier><identifier>DOI: 10.1016/S0014-2999(02)02273-2</identifier><identifier>PMID: 12354563</identifier><language>eng</language><publisher>Netherlands</publisher><subject>alpha7 Nicotinic Acetylcholine Receptor ; Animals ; Bridged Bicyclo Compounds, Heterocyclic - metabolism ; Dose-Response Relationship, Drug ; Female ; Humans ; Mice ; Nicotinic Agonists - metabolism ; Nicotinic Agonists - pharmacology ; Oocytes - metabolism ; Pyridines - metabolism ; Receptors, Nicotinic - physiology ; Receptors, Serotonin - physiology ; Receptors, Serotonin, 5-HT3 ; Serotonin Receptor Agonists - metabolism ; Serotonin Receptor Agonists - pharmacology ; Tumor Cells, Cultured ; Xenopus</subject><ispartof>European journal of pharmacology, 2002-10, Vol.452 (2), p.137-144</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12354563$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Broad, Lisa M</creatorcontrib><creatorcontrib>Felthouse, Catherine</creatorcontrib><creatorcontrib>Zwart, Ruud</creatorcontrib><creatorcontrib>McPhie, Gordon I</creatorcontrib><creatorcontrib>Pearson, Kathy H</creatorcontrib><creatorcontrib>Craig, Peter J</creatorcontrib><creatorcontrib>Wallace, Louise</creatorcontrib><creatorcontrib>Broadmore, Richard J</creatorcontrib><creatorcontrib>Boot, John R</creatorcontrib><creatorcontrib>Keenan, Martine</creatorcontrib><creatorcontrib>Baker, S Richard</creatorcontrib><creatorcontrib>Sher, Emanuele</creatorcontrib><title>PSAB-OFP, a selective alpha 7 nicotinic receptor agonist, is also a potent agonist of the 5-HT3 receptor</title><title>European journal of pharmacology</title><addtitle>Eur J Pharmacol</addtitle><description>5-Hydroxytryptamine 3 (5-HT(3)) and alpha 7 nicotinic receptors share high sequence homology and pharmacological cross-reactivity. An assessment of the potential role of alpha 7 receptors in many neurophysiological processes, and hence their therapeutic value, requires the development of selective alpha 7 receptor agonists. We used a recently reported selective alpha 7 receptor agonist, (R)-(-)-5'Phenylspiro[1-azabicyclo[2.2.2] octane-3,2'-(3'H)furo[2,3-b]pyridine (PSAB-OFP) and confirmed its activity on human recombinant alpha 7 receptors. However, PSAB-OFP also displayed high affinity binding to 5-HT(3) receptors. To assess the functional activity of PSAB-OFP on 5-HT(3) receptors we studied recombinant human 5-HT(3) receptors expressed in Xenopus oocytes, as well as native mouse 5-HT(3) receptors expressed in N1E-115 neuroblastoma cells, using whole-cell patch clamp and Ca(2+) imaging. Our results show that PSAB-OFP is an equipotent, partial agonist of both alpha 7 and 5-HT(3) receptors. We conclude that it will be necessary to identify the determinant of this overlapping pharmacology in order to develop more selective alpha 7 receptor ligands.</description><subject>alpha7 Nicotinic Acetylcholine Receptor</subject><subject>Animals</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Female</subject><subject>Humans</subject><subject>Mice</subject><subject>Nicotinic Agonists - metabolism</subject><subject>Nicotinic Agonists - pharmacology</subject><subject>Oocytes - metabolism</subject><subject>Pyridines - metabolism</subject><subject>Receptors, Nicotinic - physiology</subject><subject>Receptors, Serotonin - physiology</subject><subject>Receptors, Serotonin, 5-HT3</subject><subject>Serotonin Receptor Agonists - metabolism</subject><subject>Serotonin Receptor Agonists - pharmacology</subject><subject>Tumor Cells, Cultured</subject><subject>Xenopus</subject><issn>0014-2999</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kE1LAzEQhnNQbK3-BCUnUWg0n7vNsRa1QqGF1vOSZGdtZLtZN6ngv3fBtpd5Yd7nmcMgdMPoI6Mse1pTyiThWut7yh8o57kg_AwNT-sBuozxi1KqNFcXaMC4UFJlYoi2q_X0mSxfV2NscIQaXPI_gE3dbg3OceNdSL6fuAMHbQodNp-h8TGNsY89FkPvtSFBk44NDhVOW8CKzDfi5F2h86rH4fqQI_Tx-rKZzcli-fY-my5Iy4ROxBoJXKo8U1wLKSsz0QJKq6kWwjGumQJbTZg2ZclEJa0zzDJnuTEZdcpqMUJ3_3fbLnzvIaZi56ODujYNhH0scs6EmHDVg7cHcG93UBZt53em-y2OvxF_M0lj8g</recordid><startdate>20021004</startdate><enddate>20021004</enddate><creator>Broad, Lisa M</creator><creator>Felthouse, Catherine</creator><creator>Zwart, Ruud</creator><creator>McPhie, Gordon I</creator><creator>Pearson, Kathy H</creator><creator>Craig, Peter J</creator><creator>Wallace, Louise</creator><creator>Broadmore, Richard J</creator><creator>Boot, John R</creator><creator>Keenan, Martine</creator><creator>Baker, S Richard</creator><creator>Sher, Emanuele</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20021004</creationdate><title>PSAB-OFP, a selective alpha 7 nicotinic receptor agonist, is also a potent agonist of the 5-HT3 receptor</title><author>Broad, Lisa M ; Felthouse, Catherine ; Zwart, Ruud ; McPhie, Gordon I ; Pearson, Kathy H ; Craig, Peter J ; Wallace, Louise ; Broadmore, Richard J ; Boot, John R ; Keenan, Martine ; Baker, S Richard ; Sher, Emanuele</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p139t-ba4e24576529344fa893edb90933c12915ebf819add13f4bca1b1cb2aa60c5b93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>alpha7 Nicotinic Acetylcholine Receptor</topic><topic>Animals</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Female</topic><topic>Humans</topic><topic>Mice</topic><topic>Nicotinic Agonists - metabolism</topic><topic>Nicotinic Agonists - pharmacology</topic><topic>Oocytes - metabolism</topic><topic>Pyridines - metabolism</topic><topic>Receptors, Nicotinic - physiology</topic><topic>Receptors, Serotonin - physiology</topic><topic>Receptors, Serotonin, 5-HT3</topic><topic>Serotonin Receptor Agonists - metabolism</topic><topic>Serotonin Receptor Agonists - pharmacology</topic><topic>Tumor Cells, Cultured</topic><topic>Xenopus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Broad, Lisa M</creatorcontrib><creatorcontrib>Felthouse, Catherine</creatorcontrib><creatorcontrib>Zwart, Ruud</creatorcontrib><creatorcontrib>McPhie, Gordon I</creatorcontrib><creatorcontrib>Pearson, Kathy H</creatorcontrib><creatorcontrib>Craig, Peter J</creatorcontrib><creatorcontrib>Wallace, Louise</creatorcontrib><creatorcontrib>Broadmore, Richard J</creatorcontrib><creatorcontrib>Boot, John R</creatorcontrib><creatorcontrib>Keenan, Martine</creatorcontrib><creatorcontrib>Baker, S Richard</creatorcontrib><creatorcontrib>Sher, Emanuele</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Broad, Lisa M</au><au>Felthouse, Catherine</au><au>Zwart, Ruud</au><au>McPhie, Gordon I</au><au>Pearson, Kathy H</au><au>Craig, Peter J</au><au>Wallace, Louise</au><au>Broadmore, Richard J</au><au>Boot, John R</au><au>Keenan, Martine</au><au>Baker, S Richard</au><au>Sher, Emanuele</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PSAB-OFP, a selective alpha 7 nicotinic receptor agonist, is also a potent agonist of the 5-HT3 receptor</atitle><jtitle>European journal of pharmacology</jtitle><addtitle>Eur J Pharmacol</addtitle><date>2002-10-04</date><risdate>2002</risdate><volume>452</volume><issue>2</issue><spage>137</spage><epage>144</epage><pages>137-144</pages><issn>0014-2999</issn><abstract>5-Hydroxytryptamine 3 (5-HT(3)) and alpha 7 nicotinic receptors share high sequence homology and pharmacological cross-reactivity. An assessment of the potential role of alpha 7 receptors in many neurophysiological processes, and hence their therapeutic value, requires the development of selective alpha 7 receptor agonists. We used a recently reported selective alpha 7 receptor agonist, (R)-(-)-5'Phenylspiro[1-azabicyclo[2.2.2] octane-3,2'-(3'H)furo[2,3-b]pyridine (PSAB-OFP) and confirmed its activity on human recombinant alpha 7 receptors. However, PSAB-OFP also displayed high affinity binding to 5-HT(3) receptors. To assess the functional activity of PSAB-OFP on 5-HT(3) receptors we studied recombinant human 5-HT(3) receptors expressed in Xenopus oocytes, as well as native mouse 5-HT(3) receptors expressed in N1E-115 neuroblastoma cells, using whole-cell patch clamp and Ca(2+) imaging. Our results show that PSAB-OFP is an equipotent, partial agonist of both alpha 7 and 5-HT(3) receptors. We conclude that it will be necessary to identify the determinant of this overlapping pharmacology in order to develop more selective alpha 7 receptor ligands.</abstract><cop>Netherlands</cop><pmid>12354563</pmid><doi>10.1016/S0014-2999(02)02273-2</doi><tpages>8</tpages></addata></record> |
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| subjects | alpha7 Nicotinic Acetylcholine Receptor Animals Bridged Bicyclo Compounds, Heterocyclic - metabolism Dose-Response Relationship, Drug Female Humans Mice Nicotinic Agonists - metabolism Nicotinic Agonists - pharmacology Oocytes - metabolism Pyridines - metabolism Receptors, Nicotinic - physiology Receptors, Serotonin - physiology Receptors, Serotonin, 5-HT3 Serotonin Receptor Agonists - metabolism Serotonin Receptor Agonists - pharmacology Tumor Cells, Cultured Xenopus |
| title | PSAB-OFP, a selective alpha 7 nicotinic receptor agonist, is also a potent agonist of the 5-HT3 receptor |
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