Modulation of MAO Activity by Imidazoline and Guanidine Derivatives
I2‐binding sites (I2‐BS) are attributed to be a regulative site on monoamine oxidase (MAO). The in vivo and in vitro effects of various imidazoline and guanidine derivatives on MAO activity and on mitochondrial respiration were studied. Substances with high affinity for I2‐BS (antazoline, idazoxan,...
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| Veröffentlicht in: | Annals of the New York Academy of Sciences 1999-06, Vol.881 (1), p.313-331 |
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| creator | RAASCH, W. MUHLE, H. DOMINIAK, P. |
| description | I2‐binding sites (I2‐BS) are attributed to be a regulative site on monoamine oxidase (MAO). The in vivo and in vitro effects of various imidazoline and guanidine derivatives on MAO activity and on mitochondrial respiration were studied. Substances with high affinity for I2‐BS (antazoline, idazoxan, and cirazoline: IC50= 20.3, 33.8, and 43.4 μM) had a stronger inhibitory effect on MAO activity than did I1‐ligands (efaroxan, rilmenidine, clonidine, and moxonidine: IC50= 277, 801, 1,224, and >10,000 μM). Substances with the highest inhibitory effects were BDF8082 (IC50= 1.7 μM) and 2‐(2‐benzofuranyl)‐2‐imidazoline (BFI; IC50= 4.0 μM). The enzyme is inhibited noncompetitively and is reversible, because its activity is completely or partially restored after dialysis. Agmatine, the putative endogenous ligand for IBS, also decreased MAO activity (IC50= 168 μM), whereas its precursor, l‐arginine, and its metabolite, putrescine, had no effects. In vitro inhibition of MAO and mitochondrial respiration by the IBS‐ligands tested could not be correlated, suggesting no link between the function of the inner and outer mitochondrial membrane. MAO activity in vivo was significantly reduced only by pargyline (−95%), BDF8082 (−68%), BFI (−43%), and 1‐(m‐chlorophenyl)‐biguanide (−28%). Catecholamine content of livers obtained from animals treated with different IBS‐ligands was consequently increased. In conclusion, the strong inhibitory effects of I2 selective imidazoline ligands confirm the existence of I2‐BS as a regulatory site on MAO. |
| doi_str_mv | 10.1111/j.1749-6632.1999.tb09376.x |
| format | Article |
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The in vivo and in vitro effects of various imidazoline and guanidine derivatives on MAO activity and on mitochondrial respiration were studied. Substances with high affinity for I2‐BS (antazoline, idazoxan, and cirazoline: IC50= 20.3, 33.8, and 43.4 μM) had a stronger inhibitory effect on MAO activity than did I1‐ligands (efaroxan, rilmenidine, clonidine, and moxonidine: IC50= 277, 801, 1,224, and >10,000 μM). Substances with the highest inhibitory effects were BDF8082 (IC50= 1.7 μM) and 2‐(2‐benzofuranyl)‐2‐imidazoline (BFI; IC50= 4.0 μM). The enzyme is inhibited noncompetitively and is reversible, because its activity is completely or partially restored after dialysis. Agmatine, the putative endogenous ligand for IBS, also decreased MAO activity (IC50= 168 μM), whereas its precursor, l‐arginine, and its metabolite, putrescine, had no effects. In vitro inhibition of MAO and mitochondrial respiration by the IBS‐ligands tested could not be correlated, suggesting no link between the function of the inner and outer mitochondrial membrane. MAO activity in vivo was significantly reduced only by pargyline (−95%), BDF8082 (−68%), BFI (−43%), and 1‐(m‐chlorophenyl)‐biguanide (−28%). Catecholamine content of livers obtained from animals treated with different IBS‐ligands was consequently increased. In conclusion, the strong inhibitory effects of I2 selective imidazoline ligands confirm the existence of I2‐BS as a regulatory site on MAO.</description><identifier>ISSN: 0077-8923</identifier><identifier>EISSN: 1749-6632</identifier><identifier>DOI: 10.1111/j.1749-6632.1999.tb09376.x</identifier><identifier>PMID: 10415932</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Animals ; Binding Sites ; Brain - enzymology ; Catecholamines - metabolism ; Guanidines - pharmacology ; Imidazoles - pharmacology ; Imidazoline Receptors ; Kinetics ; Ligands ; Male ; Mitochondria, Liver - drug effects ; Mitochondria, Liver - metabolism ; Monoamine Oxidase - metabolism ; Monoamine Oxidase Inhibitors - pharmacology ; Myocardium - enzymology ; Oxygen Consumption - drug effects ; Rats ; Rats, Sprague-Dawley ; Receptors, Drug - agonists ; Receptors, Drug - physiology ; Structure-Activity Relationship</subject><ispartof>Annals of the New York Academy of Sciences, 1999-06, Vol.881 (1), p.313-331</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4423-f07a12d11cbb8d65529e26cb43420333969aa0efb23b9c1599a5fe24bf0f0d4c3</citedby><cites>FETCH-LOGICAL-c4423-f07a12d11cbb8d65529e26cb43420333969aa0efb23b9c1599a5fe24bf0f0d4c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1749-6632.1999.tb09376.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1749-6632.1999.tb09376.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10415932$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>RAASCH, W.</creatorcontrib><creatorcontrib>MUHLE, H.</creatorcontrib><creatorcontrib>DOMINIAK, P.</creatorcontrib><title>Modulation of MAO Activity by Imidazoline and Guanidine Derivatives</title><title>Annals of the New York Academy of Sciences</title><addtitle>Ann N Y Acad Sci</addtitle><description>I2‐binding sites (I2‐BS) are attributed to be a regulative site on monoamine oxidase (MAO). The in vivo and in vitro effects of various imidazoline and guanidine derivatives on MAO activity and on mitochondrial respiration were studied. Substances with high affinity for I2‐BS (antazoline, idazoxan, and cirazoline: IC50= 20.3, 33.8, and 43.4 μM) had a stronger inhibitory effect on MAO activity than did I1‐ligands (efaroxan, rilmenidine, clonidine, and moxonidine: IC50= 277, 801, 1,224, and >10,000 μM). Substances with the highest inhibitory effects were BDF8082 (IC50= 1.7 μM) and 2‐(2‐benzofuranyl)‐2‐imidazoline (BFI; IC50= 4.0 μM). The enzyme is inhibited noncompetitively and is reversible, because its activity is completely or partially restored after dialysis. Agmatine, the putative endogenous ligand for IBS, also decreased MAO activity (IC50= 168 μM), whereas its precursor, l‐arginine, and its metabolite, putrescine, had no effects. In vitro inhibition of MAO and mitochondrial respiration by the IBS‐ligands tested could not be correlated, suggesting no link between the function of the inner and outer mitochondrial membrane. MAO activity in vivo was significantly reduced only by pargyline (−95%), BDF8082 (−68%), BFI (−43%), and 1‐(m‐chlorophenyl)‐biguanide (−28%). Catecholamine content of livers obtained from animals treated with different IBS‐ligands was consequently increased. In conclusion, the strong inhibitory effects of I2 selective imidazoline ligands confirm the existence of I2‐BS as a regulatory site on MAO.</description><subject>Animals</subject><subject>Binding Sites</subject><subject>Brain - enzymology</subject><subject>Catecholamines - metabolism</subject><subject>Guanidines - pharmacology</subject><subject>Imidazoles - pharmacology</subject><subject>Imidazoline Receptors</subject><subject>Kinetics</subject><subject>Ligands</subject><subject>Male</subject><subject>Mitochondria, Liver - drug effects</subject><subject>Mitochondria, Liver - metabolism</subject><subject>Monoamine Oxidase - metabolism</subject><subject>Monoamine Oxidase Inhibitors - pharmacology</subject><subject>Myocardium - enzymology</subject><subject>Oxygen Consumption - drug effects</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Drug - agonists</subject><subject>Receptors, Drug - physiology</subject><subject>Structure-Activity Relationship</subject><issn>0077-8923</issn><issn>1749-6632</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqVkEFP2zAYhi00BKXwF6Zoh90SbH-OHe8ylQ4KUgFNAyF2sezEkdylSRcnpeHXkygV4oovn6zvfR9bD0LfCI5If85XERFMhpwDjYiUMmoMliB4tDtAk_fVFzTBWIgwkRSO0Yn3K4wJTZg4QscEMxJLoBM0v62yttCNq8qgyoPb2X0wSxu3dU0XmC64WbtMv1aFK22gyyxYtLp02XD7ZWu37Xtb60_RYa4Lb8_2c4oery4f5tfh8n5xM58tw5QxCmGOhSY0IyQ1Jsl4HFNpKU8NA0YxAEgutcY2NxSMTPv_SR3nljKT4xxnLIUp-j5yN3X1v7W-UWvnU1sUurRV6xWXEnORJH3wxxhM68r72uZqU7u1rjtFsBoUqpUaPKnBkxoUqr1CtevLX_evtGZtsw_V0Vkf-DkGXlxhu0-g1d3z7A8Q6AnhSHC-sbt3gq7_KS5AxOrpbqFg-fD3N16CuoA3gYaQMQ</recordid><startdate>199906</startdate><enddate>199906</enddate><creator>RAASCH, W.</creator><creator>MUHLE, H.</creator><creator>DOMINIAK, P.</creator><general>Blackwell Publishing Ltd</general><scope>BSCLL</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></search><sort><creationdate>199906</creationdate><title>Modulation of MAO Activity by Imidazoline and Guanidine Derivatives</title><author>RAASCH, W. ; MUHLE, H. ; DOMINIAK, P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4423-f07a12d11cbb8d65529e26cb43420333969aa0efb23b9c1599a5fe24bf0f0d4c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Animals</topic><topic>Binding Sites</topic><topic>Brain - enzymology</topic><topic>Catecholamines - metabolism</topic><topic>Guanidines - pharmacology</topic><topic>Imidazoles - pharmacology</topic><topic>Imidazoline Receptors</topic><topic>Kinetics</topic><topic>Ligands</topic><topic>Male</topic><topic>Mitochondria, Liver - drug effects</topic><topic>Mitochondria, Liver - metabolism</topic><topic>Monoamine Oxidase - metabolism</topic><topic>Monoamine Oxidase Inhibitors - pharmacology</topic><topic>Myocardium - enzymology</topic><topic>Oxygen Consumption - drug effects</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Drug - agonists</topic><topic>Receptors, Drug - physiology</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>RAASCH, W.</creatorcontrib><creatorcontrib>MUHLE, H.</creatorcontrib><creatorcontrib>DOMINIAK, P.</creatorcontrib><collection>Istex</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><jtitle>Annals of the New York Academy of Sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>RAASCH, W.</au><au>MUHLE, H.</au><au>DOMINIAK, P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Modulation of MAO Activity by Imidazoline and Guanidine Derivatives</atitle><jtitle>Annals of the New York Academy of Sciences</jtitle><addtitle>Ann N Y Acad Sci</addtitle><date>1999-06</date><risdate>1999</risdate><volume>881</volume><issue>1</issue><spage>313</spage><epage>331</epage><pages>313-331</pages><issn>0077-8923</issn><eissn>1749-6632</eissn><abstract>I2‐binding sites (I2‐BS) are attributed to be a regulative site on monoamine oxidase (MAO). The in vivo and in vitro effects of various imidazoline and guanidine derivatives on MAO activity and on mitochondrial respiration were studied. Substances with high affinity for I2‐BS (antazoline, idazoxan, and cirazoline: IC50= 20.3, 33.8, and 43.4 μM) had a stronger inhibitory effect on MAO activity than did I1‐ligands (efaroxan, rilmenidine, clonidine, and moxonidine: IC50= 277, 801, 1,224, and >10,000 μM). Substances with the highest inhibitory effects were BDF8082 (IC50= 1.7 μM) and 2‐(2‐benzofuranyl)‐2‐imidazoline (BFI; IC50= 4.0 μM). The enzyme is inhibited noncompetitively and is reversible, because its activity is completely or partially restored after dialysis. Agmatine, the putative endogenous ligand for IBS, also decreased MAO activity (IC50= 168 μM), whereas its precursor, l‐arginine, and its metabolite, putrescine, had no effects. In vitro inhibition of MAO and mitochondrial respiration by the IBS‐ligands tested could not be correlated, suggesting no link between the function of the inner and outer mitochondrial membrane. MAO activity in vivo was significantly reduced only by pargyline (−95%), BDF8082 (−68%), BFI (−43%), and 1‐(m‐chlorophenyl)‐biguanide (−28%). Catecholamine content of livers obtained from animals treated with different IBS‐ligands was consequently increased. In conclusion, the strong inhibitory effects of I2 selective imidazoline ligands confirm the existence of I2‐BS as a regulatory site on MAO.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>10415932</pmid><doi>10.1111/j.1749-6632.1999.tb09376.x</doi><tpages>19</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Binding Sites Brain - enzymology Catecholamines - metabolism Guanidines - pharmacology Imidazoles - pharmacology Imidazoline Receptors Kinetics Ligands Male Mitochondria, Liver - drug effects Mitochondria, Liver - metabolism Monoamine Oxidase - metabolism Monoamine Oxidase Inhibitors - pharmacology Myocardium - enzymology Oxygen Consumption - drug effects Rats Rats, Sprague-Dawley Receptors, Drug - agonists Receptors, Drug - physiology Structure-Activity Relationship |
| title | Modulation of MAO Activity by Imidazoline and Guanidine Derivatives |
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