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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
20
|
| pubmed:dateCreated |
1993-11-9
|
| pubmed:abstractText |
Previous studies have shown that 3 beta-(substituted phenyl)tropan-2 beta-carboxylic acid esters possess high affinity for the cocaine binding site on the dopamine transporter both in vitro and in vivo and inhibit dopamine uptake in vitro. Since 1,2,4-oxadiazoles are excellent bioisosteres of ester groups, we have prepared several 3 beta-(substituted phenyl)-2 beta-(3-substituted 1',2',4'-oxadiazol-5'-yl)tropanes (5b-h) and all four stereoisomers of (1R,5S)-3 phenyl-2-(3-methyl-1',2',4'-oxadiazol-5'-yl)tropane (5a and 6-8). The 3 alpha-phenyl-2-alpha-(3'-methyl-1',2',4'-oxadiazole) isomer 7 was prepared from a stereoselective addition of phenyllithium to (1R,5S)-2-(3'-methyl-1',2',4'-oxadiazol-5-yl)-8-methyl-8- azabicyclo[3.2.1]oct-2-ene (11). The binding affinities for 5a-h and 6-8 at the dopamine, serotonin, and norepinephrine transporters were obtained. In general these bioisosteres showed potencies for the dopamine transporter similar to those of their parent esters. 3 beta-(4'-Chlorophenyl)-2 beta-(3'-phenyl-1',2',4'-oxadiazol-5'-yl)tropane (5d) was the most potent analogue with an IC50 of 1.62nM. However, 3 beta-(4'-chlorophenyl)-2 beta-(3'-methoxyphenyl-1',2'4'- oxadiazol-5'-yl)tropane (5e) with an IC50 of 1.81 nM was the most selective analogue for the dopamine transporter showing NE/DA and 5-HT/DA ratios of 461 and 186, respectively. The cis- and trans-3 alpha-phenyl-2-(3'-methyl-1',2',4'-oxadiazol-5'-yl)tropanes (7 and 8), which exist in a boat conformation, have IC50 values only slightly greater than that of the 3 beta,2 beta-isomer (5a) which possesses the cocaine stereochemistry.
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| pubmed:grant | |
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Cocaine,
http://linkedlifedata.com/resource/pubmed/chemical/Dopamine Plasma Membrane Transport...,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Transport Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Nerve Tissue Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Norepinephrine Plasma Membrane...,
http://linkedlifedata.com/resource/pubmed/chemical/Serotonin Plasma Membrane...,
http://linkedlifedata.com/resource/pubmed/chemical/Slc6a2 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Slc6a4 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Symporters,
http://linkedlifedata.com/resource/pubmed/chemical/Tropanes
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Oct
|
| pubmed:issn |
0022-2623
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| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
1
|
| pubmed:volume |
36
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
2886-90
|
| pubmed:dateRevised |
2007-11-14
|
| pubmed:meshHeading |
pubmed-meshheading:8411004-Animals,
pubmed-meshheading:8411004-Binding Sites,
pubmed-meshheading:8411004-Brain,
pubmed-meshheading:8411004-Carrier Proteins,
pubmed-meshheading:8411004-Cocaine,
pubmed-meshheading:8411004-Dopamine Plasma Membrane Transport Proteins,
pubmed-meshheading:8411004-Male,
pubmed-meshheading:8411004-Membrane Glycoproteins,
pubmed-meshheading:8411004-Membrane Transport Proteins,
pubmed-meshheading:8411004-Molecular Structure,
pubmed-meshheading:8411004-Nerve Tissue Proteins,
pubmed-meshheading:8411004-Norepinephrine Plasma Membrane Transport Proteins,
pubmed-meshheading:8411004-Rats,
pubmed-meshheading:8411004-Rats, Sprague-Dawley,
pubmed-meshheading:8411004-Serotonin Plasma Membrane Transport Proteins,
pubmed-meshheading:8411004-Stereoisomerism,
pubmed-meshheading:8411004-Structure-Activity Relationship,
pubmed-meshheading:8411004-Symporters,
pubmed-meshheading:8411004-Tropanes
|
| pubmed:year |
1993
|
| pubmed:articleTitle |
3-Aryl-2-(3'-substituted-1',2',4'-oxadiazol-5'-yl)tropane analogues of cocaine: affinities at the cocaine binding site at the dopamine, serotonin, and norepinephrine transporters.
|
| pubmed:affiliation |
Research Triangle Institute, Research Triangle Park, North Carolina 27709.
|
| pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, U.S. Gov't, P.H.S.
|