Studies on the Monoamine Oxidase-B-Catalyzed Biotransformation of 4-Azaaryl-1-methyl-1,2,3,6-tetrahydropyridine Derivatives
The substrate properties of a series of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinyl (MPTP) analogues in which the C-4 phenyl group has been replaced with various 4-azaaryl moieties have been examined in an effort to evaluate the contribution of electronic, polar, and steric parameters to the MAO-B...
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| Veröffentlicht in: | Journal of medicinal chemistry 1999-05, Vol.42 (10), p.1828-1835 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 42 |
| creator | Nimkar, Sandeep K Mabic, Stéphane Anderson, Andrea H Palmer, Sonya L Graham, Thomas H de Jonge, Milly Hazelwood, Lisa Hislop, Sean J Castagnoli, Neal |
| description | The substrate properties of a series of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinyl (MPTP) analogues in which the C-4 phenyl group has been replaced with various 4-azaaryl moieties have been examined in an effort to evaluate the contribution of electronic, polar, and steric parameters to the MAO-B-catalyzed oxidation of this type of cyclic tertiary allylamine to the corresponding dihydropyridinium metabolite. No significant correlation could be found with the calculated energy of the C−H bond undergoing cleavage. A general trend, however, was observed between the magnitude of the log P value with the magnitude of k cat/K m. The results indicate that the placement of a polar nitrogen atom in the space occupied by the phenyl group of MPTP leads to a dramatic decrease in substrate properties. Enhanced substrate properties, however, were observed when benzoazaarenes replaced the corresponding five-membered azaarenes. These results are consistent with our previously published molecular model of the active site of MAO-B. |
| doi_str_mv | 10.1021/jm9900319 |
| format | Article |
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No significant correlation could be found with the calculated energy of the C−H bond undergoing cleavage. A general trend, however, was observed between the magnitude of the log P value with the magnitude of k cat/K m. The results indicate that the placement of a polar nitrogen atom in the space occupied by the phenyl group of MPTP leads to a dramatic decrease in substrate properties. Enhanced substrate properties, however, were observed when benzoazaarenes replaced the corresponding five-membered azaarenes. 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Med. Chem</addtitle><description>The substrate properties of a series of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinyl (MPTP) analogues in which the C-4 phenyl group has been replaced with various 4-azaaryl moieties have been examined in an effort to evaluate the contribution of electronic, polar, and steric parameters to the MAO-B-catalyzed oxidation of this type of cyclic tertiary allylamine to the corresponding dihydropyridinium metabolite. No significant correlation could be found with the calculated energy of the C−H bond undergoing cleavage. A general trend, however, was observed between the magnitude of the log P value with the magnitude of k cat/K m. The results indicate that the placement of a polar nitrogen atom in the space occupied by the phenyl group of MPTP leads to a dramatic decrease in substrate properties. Enhanced substrate properties, however, were observed when benzoazaarenes replaced the corresponding five-membered azaarenes. These results are consistent with our previously published molecular model of the active site of MAO-B.</description><subject>Analytical, structural and metabolic biochemistry</subject><subject>Animals</subject><subject>Aza Compounds - chemistry</subject><subject>Biological and medical sciences</subject><subject>Catalysis</subject><subject>Cattle</subject><subject>Enzymes and enzyme inhibitors</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Kinetics</subject><subject>Liver - chemistry</subject><subject>Monoamine Oxidase - chemistry</subject><subject>Oxidoreductases</subject><subject>Pyridines - chemistry</subject><subject>Structure-Activity Relationship</subject><subject>Substrate Specificity</subject><subject>Thermodynamics</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0EFv0zAUB3ALgVgZHPgCKAdAQqrBdhLHOW4dA6ShIVouXKyX5Fl1SeLOTqZ1fHkcpRocONmSf-8vvz8hLzl7z5ngH3ZdWTKW8vIRWfBcMJoplj0mC8aEoEKK9IQ8C2HHJiPSp-SEszSTZZovyO_1MDYWQ-L6ZNhi8tX1DjrbY3J9ZxsISM_pCgZoD_fYJOfWDR76YJzvYLBxxpkko2f3AP7QUk47HLbTZSmW6VLSASPfHhrv9gdvmyn2Ar29jbO3GJ6TJwbagC-O5yn5cflxs_pMr64_fVmdXVFICzXQqoS64FBncZtcGVQgRV0xzHmDNRiZqdzwvC5kXjCTiaapMmQsh7JSjQTD01Pyds7de3czYhh0Z0ONbQs9ujFoWRZKlqqM8N0Ma-9C8Gj03tsurqY501PT-qHpaF8dQ8eqw-YfOVcbwesjgFBDa2JvtQ1_ncpKJSZGZ2bDgHcPz-B_aVmkRa4339Z6fbkpfl58X2kR_ZvZQx30zo2-j9X9539_ABRpoV4</recordid><startdate>19990520</startdate><enddate>19990520</enddate><creator>Nimkar, Sandeep K</creator><creator>Mabic, Stéphane</creator><creator>Anderson, Andrea H</creator><creator>Palmer, Sonya L</creator><creator>Graham, Thomas H</creator><creator>de Jonge, Milly</creator><creator>Hazelwood, Lisa</creator><creator>Hislop, Sean J</creator><creator>Castagnoli, Neal</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</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>19990520</creationdate><title>Studies on the Monoamine Oxidase-B-Catalyzed Biotransformation of 4-Azaaryl-1-methyl-1,2,3,6-tetrahydropyridine Derivatives</title><author>Nimkar, Sandeep K ; Mabic, Stéphane ; Anderson, Andrea H ; Palmer, Sonya L ; Graham, Thomas H ; de Jonge, Milly ; Hazelwood, Lisa ; Hislop, Sean J ; Castagnoli, Neal</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a378t-b9ac71ac402258fe8a62cb0e51decaf6485f15c76570f42ddb4e005a9b8d6af13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Analytical, structural and metabolic biochemistry</topic><topic>Animals</topic><topic>Aza Compounds - chemistry</topic><topic>Biological and medical sciences</topic><topic>Catalysis</topic><topic>Cattle</topic><topic>Enzymes and enzyme inhibitors</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Kinetics</topic><topic>Liver - chemistry</topic><topic>Monoamine Oxidase - chemistry</topic><topic>Oxidoreductases</topic><topic>Pyridines - chemistry</topic><topic>Structure-Activity Relationship</topic><topic>Substrate Specificity</topic><topic>Thermodynamics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nimkar, Sandeep K</creatorcontrib><creatorcontrib>Mabic, Stéphane</creatorcontrib><creatorcontrib>Anderson, Andrea H</creatorcontrib><creatorcontrib>Palmer, Sonya L</creatorcontrib><creatorcontrib>Graham, Thomas H</creatorcontrib><creatorcontrib>de Jonge, Milly</creatorcontrib><creatorcontrib>Hazelwood, Lisa</creatorcontrib><creatorcontrib>Hislop, Sean J</creatorcontrib><creatorcontrib>Castagnoli, Neal</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nimkar, Sandeep K</au><au>Mabic, Stéphane</au><au>Anderson, Andrea H</au><au>Palmer, Sonya L</au><au>Graham, Thomas H</au><au>de Jonge, Milly</au><au>Hazelwood, Lisa</au><au>Hislop, Sean J</au><au>Castagnoli, Neal</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Studies on the Monoamine Oxidase-B-Catalyzed Biotransformation of 4-Azaaryl-1-methyl-1,2,3,6-tetrahydropyridine Derivatives</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. 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The results indicate that the placement of a polar nitrogen atom in the space occupied by the phenyl group of MPTP leads to a dramatic decrease in substrate properties. Enhanced substrate properties, however, were observed when benzoazaarenes replaced the corresponding five-membered azaarenes. These results are consistent with our previously published molecular model of the active site of MAO-B.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>10346935</pmid><doi>10.1021/jm9900319</doi><tpages>8</tpages></addata></record> |
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| subjects | Analytical, structural and metabolic biochemistry Animals Aza Compounds - chemistry Biological and medical sciences Catalysis Cattle Enzymes and enzyme inhibitors Fundamental and applied biological sciences. Psychology Kinetics Liver - chemistry Monoamine Oxidase - chemistry Oxidoreductases Pyridines - chemistry Structure-Activity Relationship Substrate Specificity Thermodynamics |
| title | Studies on the Monoamine Oxidase-B-Catalyzed Biotransformation of 4-Azaaryl-1-methyl-1,2,3,6-tetrahydropyridine Derivatives |
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