Source:http://linkedlifedata.com/resource/pubmed/id/10543879
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
21
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pubmed:dateCreated |
1999-11-22
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pubmed:abstractText |
An enantiospecific method was developed for the synthesis of 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-7-substituted-1,2,3,4-tetrahydroisoquinolines (THIQs) from phenylalanine. Biochemical evaluation of the enantiomers of these compounds at both PNMT and the alpha(2)-adrenoceptor indicates that both sites display similar stereoselectivity. Overall the R-enantiomer was usually the more potent enantiomer at both PNMT and the alpha(2)-adrenoceptor for these 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-THIQs. The one exception is 3-hydroxymethyl-7-nitro-THIQ (9), which was found to display the opposite stereoselectivity at the alpha(2)-adrenoceptor. A comparison of the PNMT inhibitory potency of the enantiomers of these 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-THIQs indicates that all of the 3-substituted-THIQs displayed similar inhibitory potency for PNMT. However, the nature of the 3-substituent was found to have a major effect on the alpha(2)-adrenoceptor affinity of these compounds with the 3-hydroxymethyl- and 3-fluoromethyl-THIQs having the highest affinity and THIQs containing the 3-chloromethyl moiety the least. Compounds R-3-fluoromethyl-7-cyano-THIQ (R-12) and R-3-fluoromethyl-7-N-(4-chlorophenyl)aminosulfonyl-THIQ (R-13) and both enantiomers of 3-chloromethyl-7-nitro-THIQ (R- and S-30) are the most selective inhibitors in this study and display selectivities (alpha(2)-adrenoceptor K(i)/PNMT K(i)) greater than 200. These compounds give important insight into the steric and stereochemical preferences of both PNMT and the alpha(2)-adrenoceptor, which should assist in the development of new PNMT inhibitors.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adrenergic alpha-Antagonists,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Isoquinolines,
http://linkedlifedata.com/resource/pubmed/chemical/Phenylethanolamine...,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Adrenergic, alpha-2,
http://linkedlifedata.com/resource/pubmed/chemical/Tetrahydroisoquinolines
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
0022-2623
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
21
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pubmed:volume |
42
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4351-61
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:10543879-Adrenergic alpha-Antagonists,
pubmed-meshheading:10543879-Animals,
pubmed-meshheading:10543879-Cattle,
pubmed-meshheading:10543879-Cerebral Cortex,
pubmed-meshheading:10543879-Enzyme Inhibitors,
pubmed-meshheading:10543879-Isoquinolines,
pubmed-meshheading:10543879-Male,
pubmed-meshheading:10543879-Models, Molecular,
pubmed-meshheading:10543879-Phenylethanolamine N-Methyltransferase,
pubmed-meshheading:10543879-Radioligand Assay,
pubmed-meshheading:10543879-Rats,
pubmed-meshheading:10543879-Rats, Sprague-Dawley,
pubmed-meshheading:10543879-Receptors, Adrenergic, alpha-2,
pubmed-meshheading:10543879-Stereoisomerism,
pubmed-meshheading:10543879-Structure-Activity Relationship,
pubmed-meshheading:10543879-Tetrahydroisoquinolines
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pubmed:year |
1999
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pubmed:articleTitle |
Enantiospecific synthesis of 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-1,2,3,4-tetrahydroisoquinolines as selective inhibitors of phenylethanolamine N-methyltransferase versus the alpha(2)-adrenoceptor.
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pubmed:affiliation |
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, USA. ggrunewald@ukans.edu
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pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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