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Milameline (CI-979/RU35926): A Muscarinic Receptor Agonist with Cognition-Activating Properties: Biochemical and In Vivo Characterization
Milameline ( E -1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxaldehyde, O -methyloxime monohydrochloride, CI-979, PD129409, RU35926) was characterized in vitro and evaluated for effects on central and peripheral cholinergic activity in rats and rhesus monkeys. In muscarinic binding studies, milameline...
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| Published in: | The Journal of pharmacology and experimental therapeutics 1999-11, Vol.291 (2), p.812-822 |
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| container_title | The Journal of pharmacology and experimental therapeutics |
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| creator | Schwarz, R D Callahan, M J Coughenour, L L Dickerson, M R Kinsora, J J Lipinski, W J Raby, C A Spencer, C J Tecle, H |
| description | Milameline ( E -1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxaldehyde, O -methyloxime monohydrochloride, CI-979, PD129409, RU35926) was characterized in vitro and evaluated for effects on central
and peripheral cholinergic activity in rats and rhesus monkeys. In muscarinic binding studies, milameline displayed nanomolar
affinity with an agonist ligand and micromolar affinity with antagonist ligands, with approximately equal affinities determined
at the five subtypes of human muscarinic receptors (hM 1 âhM 5 ) with whole cells or membranes from stably transfected Chinese hamster ovary (CHO) cells. On binding, milameline stimulated
phosphatidylinositol hydrolysis in hM 1 and hM 3 CHO cells and inhibited forskolin-activated cAMP accumulation in hM 2 and hM 4 CHO cells. Additionally, it decreased K + -stimulated release of [ 3 H]acetylcholine from rat cortical slices. Responses were not caused by the inhibition of acetylcholinesterase, and there was
no significant binding to â¼30 other neurotransmitter binding sites. In rats, milameline decreased spontaneous and scopolamine-induced
swimming activity, improved water-maze performance of animals impaired by basal forebrain lesions, increased cortical blood
flow, decreased core body temperature, and increased gastrointestinal motility. Electroencephalogram activity in both rats
and monkeys was characterized by a predominance of low-voltage desynchronized activity consistent with an increase in arousal.
Milameline also reversed a scopolamine-induced impairment of attention on a continuous-performance task in monkeys. Thus,
milameline possesses a pharmacological profile consistent with that of a partial muscarinic agonist, with central cholinergic
actions being produced in rats and monkeys at doses slightly lower than those stimulating peripheral cholinergic receptors. |
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and peripheral cholinergic activity in rats and rhesus monkeys. In muscarinic binding studies, milameline displayed nanomolar
affinity with an agonist ligand and micromolar affinity with antagonist ligands, with approximately equal affinities determined
at the five subtypes of human muscarinic receptors (hM 1 âhM 5 ) with whole cells or membranes from stably transfected Chinese hamster ovary (CHO) cells. On binding, milameline stimulated
phosphatidylinositol hydrolysis in hM 1 and hM 3 CHO cells and inhibited forskolin-activated cAMP accumulation in hM 2 and hM 4 CHO cells. Additionally, it decreased K + -stimulated release of [ 3 H]acetylcholine from rat cortical slices. Responses were not caused by the inhibition of acetylcholinesterase, and there was
no significant binding to â¼30 other neurotransmitter binding sites. In rats, milameline decreased spontaneous and scopolamine-induced
swimming activity, improved water-maze performance of animals impaired by basal forebrain lesions, increased cortical blood
flow, decreased core body temperature, and increased gastrointestinal motility. Electroencephalogram activity in both rats
and monkeys was characterized by a predominance of low-voltage desynchronized activity consistent with an increase in arousal.
Milameline also reversed a scopolamine-induced impairment of attention on a continuous-performance task in monkeys. Thus,
milameline possesses a pharmacological profile consistent with that of a partial muscarinic agonist, with central cholinergic
actions being produced in rats and monkeys at doses slightly lower than those stimulating peripheral cholinergic receptors.</description><identifier>ISSN: 0022-3565</identifier><identifier>EISSN: 1521-0103</identifier><identifier>PMID: 10525104</identifier><language>eng</language><publisher>United States: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Acetylcholine - secretion ; Animals ; Behavior, Animal - drug effects ; Binding Sites ; Cerebral Cortex - drug effects ; CHO Cells ; Cholinesterase Inhibitors - pharmacology ; Cognition - drug effects ; Colforsin - metabolism ; Cricetinae ; Cyclic AMP ; Dihydropyridines - pharmacology ; Dose-Response Relationship, Drug ; Electroencephalography - drug effects ; Humans ; In Vitro Techniques ; Macaca mulatta ; Male ; Muscarinic Agonists - pharmacology ; Neurotransmitter Agents - metabolism ; Oximes - pharmacology ; Phosphatidylinositols - metabolism ; Potassium - physiology ; Rats ; Rats, Long-Evans ; Receptors, Muscarinic - drug effects ; Scopolamine Hydrobromide - pharmacology ; Time Factors ; Transfection</subject><ispartof>The Journal of pharmacology and experimental therapeutics, 1999-11, Vol.291 (2), p.812-822</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10525104$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schwarz, R D</creatorcontrib><creatorcontrib>Callahan, M J</creatorcontrib><creatorcontrib>Coughenour, L L</creatorcontrib><creatorcontrib>Dickerson, M R</creatorcontrib><creatorcontrib>Kinsora, J J</creatorcontrib><creatorcontrib>Lipinski, W J</creatorcontrib><creatorcontrib>Raby, C A</creatorcontrib><creatorcontrib>Spencer, C J</creatorcontrib><creatorcontrib>Tecle, H</creatorcontrib><title>Milameline (CI-979/RU35926): A Muscarinic Receptor Agonist with Cognition-Activating Properties: Biochemical and In Vivo Characterization</title><title>The Journal of pharmacology and experimental therapeutics</title><addtitle>J Pharmacol Exp Ther</addtitle><description>Milameline ( E -1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxaldehyde, O -methyloxime monohydrochloride, CI-979, PD129409, RU35926) was characterized in vitro and evaluated for effects on central
and peripheral cholinergic activity in rats and rhesus monkeys. In muscarinic binding studies, milameline displayed nanomolar
affinity with an agonist ligand and micromolar affinity with antagonist ligands, with approximately equal affinities determined
at the five subtypes of human muscarinic receptors (hM 1 âhM 5 ) with whole cells or membranes from stably transfected Chinese hamster ovary (CHO) cells. On binding, milameline stimulated
phosphatidylinositol hydrolysis in hM 1 and hM 3 CHO cells and inhibited forskolin-activated cAMP accumulation in hM 2 and hM 4 CHO cells. Additionally, it decreased K + -stimulated release of [ 3 H]acetylcholine from rat cortical slices. Responses were not caused by the inhibition of acetylcholinesterase, and there was
no significant binding to â¼30 other neurotransmitter binding sites. In rats, milameline decreased spontaneous and scopolamine-induced
swimming activity, improved water-maze performance of animals impaired by basal forebrain lesions, increased cortical blood
flow, decreased core body temperature, and increased gastrointestinal motility. Electroencephalogram activity in both rats
and monkeys was characterized by a predominance of low-voltage desynchronized activity consistent with an increase in arousal.
Milameline also reversed a scopolamine-induced impairment of attention on a continuous-performance task in monkeys. Thus,
milameline possesses a pharmacological profile consistent with that of a partial muscarinic agonist, with central cholinergic
actions being produced in rats and monkeys at doses slightly lower than those stimulating peripheral cholinergic receptors.</description><subject>Acetylcholine - secretion</subject><subject>Animals</subject><subject>Behavior, Animal - drug effects</subject><subject>Binding Sites</subject><subject>Cerebral Cortex - drug effects</subject><subject>CHO Cells</subject><subject>Cholinesterase Inhibitors - pharmacology</subject><subject>Cognition - drug effects</subject><subject>Colforsin - metabolism</subject><subject>Cricetinae</subject><subject>Cyclic AMP</subject><subject>Dihydropyridines - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Electroencephalography - drug effects</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Macaca mulatta</subject><subject>Male</subject><subject>Muscarinic Agonists - pharmacology</subject><subject>Neurotransmitter Agents - metabolism</subject><subject>Oximes - pharmacology</subject><subject>Phosphatidylinositols - metabolism</subject><subject>Potassium - physiology</subject><subject>Rats</subject><subject>Rats, Long-Evans</subject><subject>Receptors, Muscarinic - drug effects</subject><subject>Scopolamine Hydrobromide - pharmacology</subject><subject>Time Factors</subject><subject>Transfection</subject><issn>0022-3565</issn><issn>1521-0103</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><recordid>eNpFkM9O20AYxK0KRELaV6j2VNGDxf51vNxSq0AkEBWivVpf1mv7q-xdd3cDCm_AWzeIIE4zh5mfNPMpmzPFWU4ZFUfZnFLOc6EKNctOY_xLKZOyECfZjFHFFaNynr3c4gCjHdBZclatc73U5_e_hdK8-H5BVuR2Gw0EdGjIvTV2Sj6QVecdxkSeMPWk8p3DhN7lK5PwERK6jvwKfrIhoY0X5Ad609sRDQwEXEPWjvzBR0-qHgKYZAM-w2v_c3bcwhDtl4MusofLnw_VdX5zd7WuVjd5z0WZcsM2otFKGwYg27aVy0LpgkquBXAFwtAGZCOVZEtmhC323piGs1aWm0Jbsci-vWGn4P9tbUz1iNHYYQBn_TbWS1oqVtJyH_x6CG43o23qKeAIYVe_f_dB6rHrnzDYetpPGsH4wXe7mmtW87pkXPwHOoR4nQ</recordid><startdate>19991101</startdate><enddate>19991101</enddate><creator>Schwarz, R D</creator><creator>Callahan, M J</creator><creator>Coughenour, L L</creator><creator>Dickerson, M R</creator><creator>Kinsora, J J</creator><creator>Lipinski, W J</creator><creator>Raby, C A</creator><creator>Spencer, C J</creator><creator>Tecle, H</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>19991101</creationdate><title>Milameline (CI-979/RU35926): A Muscarinic Receptor Agonist with Cognition-Activating Properties: Biochemical and In Vivo Characterization</title><author>Schwarz, R D ; Callahan, M J ; Coughenour, L L ; Dickerson, M R ; Kinsora, J J ; Lipinski, W J ; Raby, C A ; Spencer, C J ; Tecle, H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h238t-c1b3d959c1aa4fff47659604293a25a3c0da4d454171c3e64d4ccd21f48b69e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Acetylcholine - secretion</topic><topic>Animals</topic><topic>Behavior, Animal - drug effects</topic><topic>Binding Sites</topic><topic>Cerebral Cortex - drug effects</topic><topic>CHO Cells</topic><topic>Cholinesterase Inhibitors - pharmacology</topic><topic>Cognition - drug effects</topic><topic>Colforsin - metabolism</topic><topic>Cricetinae</topic><topic>Cyclic AMP</topic><topic>Dihydropyridines - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Electroencephalography - drug effects</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Macaca mulatta</topic><topic>Male</topic><topic>Muscarinic Agonists - pharmacology</topic><topic>Neurotransmitter Agents - metabolism</topic><topic>Oximes - pharmacology</topic><topic>Phosphatidylinositols - metabolism</topic><topic>Potassium - physiology</topic><topic>Rats</topic><topic>Rats, Long-Evans</topic><topic>Receptors, Muscarinic - drug effects</topic><topic>Scopolamine Hydrobromide - pharmacology</topic><topic>Time Factors</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schwarz, R D</creatorcontrib><creatorcontrib>Callahan, M J</creatorcontrib><creatorcontrib>Coughenour, L L</creatorcontrib><creatorcontrib>Dickerson, M R</creatorcontrib><creatorcontrib>Kinsora, J J</creatorcontrib><creatorcontrib>Lipinski, W J</creatorcontrib><creatorcontrib>Raby, C A</creatorcontrib><creatorcontrib>Spencer, C J</creatorcontrib><creatorcontrib>Tecle, H</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>Schwarz, R D</au><au>Callahan, M J</au><au>Coughenour, L L</au><au>Dickerson, M R</au><au>Kinsora, J J</au><au>Lipinski, W J</au><au>Raby, C A</au><au>Spencer, C J</au><au>Tecle, H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Milameline (CI-979/RU35926): A Muscarinic Receptor Agonist with Cognition-Activating Properties: Biochemical and In Vivo Characterization</atitle><jtitle>The Journal of pharmacology and experimental therapeutics</jtitle><addtitle>J Pharmacol Exp Ther</addtitle><date>1999-11-01</date><risdate>1999</risdate><volume>291</volume><issue>2</issue><spage>812</spage><epage>822</epage><pages>812-822</pages><issn>0022-3565</issn><eissn>1521-0103</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Milameline ( E -1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxaldehyde, O -methyloxime monohydrochloride, CI-979, PD129409, RU35926) was characterized in vitro and evaluated for effects on central
and peripheral cholinergic activity in rats and rhesus monkeys. In muscarinic binding studies, milameline displayed nanomolar
affinity with an agonist ligand and micromolar affinity with antagonist ligands, with approximately equal affinities determined
at the five subtypes of human muscarinic receptors (hM 1 âhM 5 ) with whole cells or membranes from stably transfected Chinese hamster ovary (CHO) cells. On binding, milameline stimulated
phosphatidylinositol hydrolysis in hM 1 and hM 3 CHO cells and inhibited forskolin-activated cAMP accumulation in hM 2 and hM 4 CHO cells. Additionally, it decreased K + -stimulated release of [ 3 H]acetylcholine from rat cortical slices. Responses were not caused by the inhibition of acetylcholinesterase, and there was
no significant binding to â¼30 other neurotransmitter binding sites. In rats, milameline decreased spontaneous and scopolamine-induced
swimming activity, improved water-maze performance of animals impaired by basal forebrain lesions, increased cortical blood
flow, decreased core body temperature, and increased gastrointestinal motility. Electroencephalogram activity in both rats
and monkeys was characterized by a predominance of low-voltage desynchronized activity consistent with an increase in arousal.
Milameline also reversed a scopolamine-induced impairment of attention on a continuous-performance task in monkeys. Thus,
milameline possesses a pharmacological profile consistent with that of a partial muscarinic agonist, with central cholinergic
actions being produced in rats and monkeys at doses slightly lower than those stimulating peripheral cholinergic receptors.</abstract><cop>United States</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>10525104</pmid><tpages>11</tpages></addata></record> |
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| identifier | ISSN: 0022-3565 |
| ispartof | The Journal of pharmacology and experimental therapeutics, 1999-11, Vol.291 (2), p.812-822 |
| issn | 0022-3565 1521-0103 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_70851808 |
| source | Freely Accessible Journals |
| subjects | Acetylcholine - secretion Animals Behavior, Animal - drug effects Binding Sites Cerebral Cortex - drug effects CHO Cells Cholinesterase Inhibitors - pharmacology Cognition - drug effects Colforsin - metabolism Cricetinae Cyclic AMP Dihydropyridines - pharmacology Dose-Response Relationship, Drug Electroencephalography - drug effects Humans In Vitro Techniques Macaca mulatta Male Muscarinic Agonists - pharmacology Neurotransmitter Agents - metabolism Oximes - pharmacology Phosphatidylinositols - metabolism Potassium - physiology Rats Rats, Long-Evans Receptors, Muscarinic - drug effects Scopolamine Hydrobromide - pharmacology Time Factors Transfection |
| title | Milameline (CI-979/RU35926): A Muscarinic Receptor Agonist with Cognition-Activating Properties: Biochemical and In Vivo Characterization |
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