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Pharmacological Analysis of the Novel Mode of Interaction between Xanomeline and the M1 Muscarinic Acetylcholine Receptor
Previous findings in our laboratory suggested that the M 1 muscarinic acetylcholine receptor (mAChR) agonist xanomeline exhibits a novel mode of interaction that involves persistent binding to and activation of the M 1 mAChR, subsequent to extensive washout, as well as a possible insurmountable elem...
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| Published in: | The Journal of pharmacology and experimental therapeutics 1999-06, Vol.289 (3), p.1220-1228 |
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| container_end_page | 1228 |
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| container_title | The Journal of pharmacology and experimental therapeutics |
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| creator | Christopoulos, A Parsons, A M El-Fakahany, E E |
| description | Previous findings in our laboratory suggested that the M 1 muscarinic acetylcholine receptor (mAChR) agonist xanomeline exhibits a novel mode of interaction that involves persistent
binding to and activation of the M 1 mAChR, subsequent to extensive washout, as well as a possible insurmountable element. In the present study, we examined this
interaction in greater detail, using Chinese hamster ovary cells transfected with the genes for the M 1 mAChR and neuronal nitric oxide synthase. Pretreatment of cells with xanomeline, followed by extensive washout, resulted in
elevated basal levels of neuronal nitric oxide synthase activity that were suppressed by the antagonists atropine or pirenzepine
in a concentration-dependent manner. Analysis of the data yielded estimates of Schild slope factors and p K B values for the antagonists that were consistent with a model of simple competition between these latter agents and the persistently
bound form of xanomeline. The ability of the antagonists to produce parallel dextral shifts of the concentration-response
curves to carbachol and xanomeline was also investigated. The interaction between xanomeline and pirenzepine appeared to be
insurmountable, but this may have been due to an equilibrium artifact. In contrast, the interaction between xanomeline and
atropine conformed to a model of competition, indicating that the mode of interaction of free xanomeline at the M 1 mAChR is pharmacologically identical with that of the persistently bound form. Radioligand binding studies also showed that
the presence of various concentrations of xanomeline had no significant effect on the calculated affinity of atropine or pirenzepine
in inhibiting the binding of [ 3 H] N -methylscopolamine. Overall, these findings suggest that the persistent attachment of xanomeline to the M 1 mAChR does not prevent this agonist from interacting with the classic binding site in a competitive fashion. |
| format | article |
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binding to and activation of the M 1 mAChR, subsequent to extensive washout, as well as a possible insurmountable element. In the present study, we examined this
interaction in greater detail, using Chinese hamster ovary cells transfected with the genes for the M 1 mAChR and neuronal nitric oxide synthase. Pretreatment of cells with xanomeline, followed by extensive washout, resulted in
elevated basal levels of neuronal nitric oxide synthase activity that were suppressed by the antagonists atropine or pirenzepine
in a concentration-dependent manner. Analysis of the data yielded estimates of Schild slope factors and p K B values for the antagonists that were consistent with a model of simple competition between these latter agents and the persistently
bound form of xanomeline. The ability of the antagonists to produce parallel dextral shifts of the concentration-response
curves to carbachol and xanomeline was also investigated. The interaction between xanomeline and pirenzepine appeared to be
insurmountable, but this may have been due to an equilibrium artifact. In contrast, the interaction between xanomeline and
atropine conformed to a model of competition, indicating that the mode of interaction of free xanomeline at the M 1 mAChR is pharmacologically identical with that of the persistently bound form. Radioligand binding studies also showed that
the presence of various concentrations of xanomeline had no significant effect on the calculated affinity of atropine or pirenzepine
in inhibiting the binding of [ 3 H] N -methylscopolamine. Overall, these findings suggest that the persistent attachment of xanomeline to the M 1 mAChR does not prevent this agonist from interacting with the classic binding site in a competitive fashion.</description><identifier>ISSN: 0022-3565</identifier><identifier>EISSN: 1521-0103</identifier><identifier>PMID: 10336509</identifier><language>eng</language><publisher>United States: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Animals ; Atropine - pharmacology ; Binding, Competitive ; Carbachol - pharmacology ; CHO Cells ; Citrulline - metabolism ; Cricetinae ; Humans ; Kinetics ; Muscarinic Agonists - pharmacology ; N-Methylscopolamine - pharmacokinetics ; Nitric Oxide Synthase - genetics ; Nitric Oxide Synthase - metabolism ; Nitric Oxide Synthase Type I ; Pirenzepine - pharmacology ; Pyridines - pharmacology ; Radioligand Assay ; Receptor, Muscarinic M1 ; Receptors, Muscarinic - genetics ; Receptors, Muscarinic - metabolism ; Receptors, Muscarinic - physiology ; Recombinant Proteins - metabolism ; Thiadiazoles - pharmacology ; Transfection ; Tritium</subject><ispartof>The Journal of pharmacology and experimental therapeutics, 1999-06, Vol.289 (3), p.1220-1228</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,783,787</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10336509$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Christopoulos, A</creatorcontrib><creatorcontrib>Parsons, A M</creatorcontrib><creatorcontrib>El-Fakahany, E E</creatorcontrib><title>Pharmacological Analysis of the Novel Mode of Interaction between Xanomeline and the M1 Muscarinic Acetylcholine Receptor</title><title>The Journal of pharmacology and experimental therapeutics</title><addtitle>J Pharmacol Exp Ther</addtitle><description>Previous findings in our laboratory suggested that the M 1 muscarinic acetylcholine receptor (mAChR) agonist xanomeline exhibits a novel mode of interaction that involves persistent
binding to and activation of the M 1 mAChR, subsequent to extensive washout, as well as a possible insurmountable element. In the present study, we examined this
interaction in greater detail, using Chinese hamster ovary cells transfected with the genes for the M 1 mAChR and neuronal nitric oxide synthase. Pretreatment of cells with xanomeline, followed by extensive washout, resulted in
elevated basal levels of neuronal nitric oxide synthase activity that were suppressed by the antagonists atropine or pirenzepine
in a concentration-dependent manner. Analysis of the data yielded estimates of Schild slope factors and p K B values for the antagonists that were consistent with a model of simple competition between these latter agents and the persistently
bound form of xanomeline. The ability of the antagonists to produce parallel dextral shifts of the concentration-response
curves to carbachol and xanomeline was also investigated. The interaction between xanomeline and pirenzepine appeared to be
insurmountable, but this may have been due to an equilibrium artifact. In contrast, the interaction between xanomeline and
atropine conformed to a model of competition, indicating that the mode of interaction of free xanomeline at the M 1 mAChR is pharmacologically identical with that of the persistently bound form. Radioligand binding studies also showed that
the presence of various concentrations of xanomeline had no significant effect on the calculated affinity of atropine or pirenzepine
in inhibiting the binding of [ 3 H] N -methylscopolamine. Overall, these findings suggest that the persistent attachment of xanomeline to the M 1 mAChR does not prevent this agonist from interacting with the classic binding site in a competitive fashion.</description><subject>Animals</subject><subject>Atropine - pharmacology</subject><subject>Binding, Competitive</subject><subject>Carbachol - pharmacology</subject><subject>CHO Cells</subject><subject>Citrulline - metabolism</subject><subject>Cricetinae</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Muscarinic Agonists - pharmacology</subject><subject>N-Methylscopolamine - pharmacokinetics</subject><subject>Nitric Oxide Synthase - genetics</subject><subject>Nitric Oxide Synthase - metabolism</subject><subject>Nitric Oxide Synthase Type I</subject><subject>Pirenzepine - pharmacology</subject><subject>Pyridines - pharmacology</subject><subject>Radioligand Assay</subject><subject>Receptor, Muscarinic M1</subject><subject>Receptors, Muscarinic - genetics</subject><subject>Receptors, Muscarinic - metabolism</subject><subject>Receptors, Muscarinic - physiology</subject><subject>Recombinant Proteins - metabolism</subject><subject>Thiadiazoles - pharmacology</subject><subject>Transfection</subject><subject>Tritium</subject><issn>0022-3565</issn><issn>1521-0103</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><recordid>eNpF0F1LwzAUBuAgipvTvyC50qtCPpq0vRzDj8GmIgrelTQ9WyNpUpPO0X_v3CZeHTjnec_Fe4LGVDCaEEr4KRoTwljChRQjdBHjJyE0TSU_R6PdmUtBijEaXhoVWqW99WujlcVTp-wQTcR-hfsG8JP_BouXvobfzdz1EJTujXe4gn4L4PCHcr4Faxxg5ep9aEnxchO1CsYZjaca-sHqxu_NK2joeh8u0dlK2QhXxzlB7_d3b7PHZPH8MJ9NF0lDRdonlOgspTWVVVXlsia6KogQjKQ5UMYVFCvIcslplmuh64ISUFwwSSqgmtVK8gm6Ofztgv_aQOzL1kQN1ioHfhNLWWSZLFi6g9dHuKlaqMsumFaFofwrawduD6Ax62ZrApTdf3lDyfKi5CVljPAfdj51MQ</recordid><startdate>19990601</startdate><enddate>19990601</enddate><creator>Christopoulos, A</creator><creator>Parsons, A M</creator><creator>El-Fakahany, E E</creator><general>American Society for Pharmacology and Experimental Therapeutics</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>19990601</creationdate><title>Pharmacological Analysis of the Novel Mode of Interaction between Xanomeline and the M1 Muscarinic Acetylcholine Receptor</title><author>Christopoulos, A ; Parsons, A M ; El-Fakahany, E E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h154t-10c741d16bbb86d0cb90552048e123ae9fe7863178c5cd910ea35260be1c2da63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Animals</topic><topic>Atropine - pharmacology</topic><topic>Binding, Competitive</topic><topic>Carbachol - pharmacology</topic><topic>CHO Cells</topic><topic>Citrulline - metabolism</topic><topic>Cricetinae</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Muscarinic Agonists - pharmacology</topic><topic>N-Methylscopolamine - pharmacokinetics</topic><topic>Nitric Oxide Synthase - genetics</topic><topic>Nitric Oxide Synthase - metabolism</topic><topic>Nitric Oxide Synthase Type I</topic><topic>Pirenzepine - pharmacology</topic><topic>Pyridines - pharmacology</topic><topic>Radioligand Assay</topic><topic>Receptor, Muscarinic M1</topic><topic>Receptors, Muscarinic - genetics</topic><topic>Receptors, Muscarinic - metabolism</topic><topic>Receptors, Muscarinic - physiology</topic><topic>Recombinant Proteins - metabolism</topic><topic>Thiadiazoles - pharmacology</topic><topic>Transfection</topic><topic>Tritium</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Christopoulos, A</creatorcontrib><creatorcontrib>Parsons, A M</creatorcontrib><creatorcontrib>El-Fakahany, E E</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>The Journal of pharmacology and experimental therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Christopoulos, A</au><au>Parsons, A M</au><au>El-Fakahany, E E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacological Analysis of the Novel Mode of Interaction between Xanomeline and the M1 Muscarinic Acetylcholine Receptor</atitle><jtitle>The Journal of pharmacology and experimental therapeutics</jtitle><addtitle>J Pharmacol Exp Ther</addtitle><date>1999-06-01</date><risdate>1999</risdate><volume>289</volume><issue>3</issue><spage>1220</spage><epage>1228</epage><pages>1220-1228</pages><issn>0022-3565</issn><eissn>1521-0103</eissn><abstract>Previous findings in our laboratory suggested that the M 1 muscarinic acetylcholine receptor (mAChR) agonist xanomeline exhibits a novel mode of interaction that involves persistent
binding to and activation of the M 1 mAChR, subsequent to extensive washout, as well as a possible insurmountable element. In the present study, we examined this
interaction in greater detail, using Chinese hamster ovary cells transfected with the genes for the M 1 mAChR and neuronal nitric oxide synthase. Pretreatment of cells with xanomeline, followed by extensive washout, resulted in
elevated basal levels of neuronal nitric oxide synthase activity that were suppressed by the antagonists atropine or pirenzepine
in a concentration-dependent manner. Analysis of the data yielded estimates of Schild slope factors and p K B values for the antagonists that were consistent with a model of simple competition between these latter agents and the persistently
bound form of xanomeline. The ability of the antagonists to produce parallel dextral shifts of the concentration-response
curves to carbachol and xanomeline was also investigated. The interaction between xanomeline and pirenzepine appeared to be
insurmountable, but this may have been due to an equilibrium artifact. In contrast, the interaction between xanomeline and
atropine conformed to a model of competition, indicating that the mode of interaction of free xanomeline at the M 1 mAChR is pharmacologically identical with that of the persistently bound form. Radioligand binding studies also showed that
the presence of various concentrations of xanomeline had no significant effect on the calculated affinity of atropine or pirenzepine
in inhibiting the binding of [ 3 H] N -methylscopolamine. Overall, these findings suggest that the persistent attachment of xanomeline to the M 1 mAChR does not prevent this agonist from interacting with the classic binding site in a competitive fashion.</abstract><cop>United States</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>10336509</pmid><tpages>9</tpages></addata></record> |
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| language | eng |
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| source | Freely Accessible Medical Journals |
| subjects | Animals Atropine - pharmacology Binding, Competitive Carbachol - pharmacology CHO Cells Citrulline - metabolism Cricetinae Humans Kinetics Muscarinic Agonists - pharmacology N-Methylscopolamine - pharmacokinetics Nitric Oxide Synthase - genetics Nitric Oxide Synthase - metabolism Nitric Oxide Synthase Type I Pirenzepine - pharmacology Pyridines - pharmacology Radioligand Assay Receptor, Muscarinic M1 Receptors, Muscarinic - genetics Receptors, Muscarinic - metabolism Receptors, Muscarinic - physiology Recombinant Proteins - metabolism Thiadiazoles - pharmacology Transfection Tritium |
| title | Pharmacological Analysis of the Novel Mode of Interaction between Xanomeline and the M1 Muscarinic Acetylcholine Receptor |
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