Source:http://linkedlifedata.com/resource/pubmed/id/10072685
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
5
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pubmed:dateCreated |
1999-4-13
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pubmed:abstractText |
As part of a program to develop site-specific medications for cocaine abuse, a series of 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane derivatives was synthesized and tested for inhibitory potency in [3H]WIN 35,428 binding and [3H]dopamine uptake assays using rat striatal tissue. Selected compounds were tested for their ability to substitute for cocaine in rat drug discrimination tests. Synthesis was accomplished by a series of Diels-Alder reactions, using cis- and trans-cinnamic acid derivatives (nitrile, acid, acid chloride) with cyclohexadiene and cyclopentadiene. Standard manipulations produced the aminomethyl side chain. Many of the compounds bound with high affinity (median IC50 = 223 nM) to the cocaine binding site as marked by [3H]WIN 35,428. Potency in the binding assay was strongly enhanced by chlorine atoms in the 3- and/or 4-position on the aromatic ring and was little affected by corresponding methoxy groups. In the [2.2.2] series there was little difference in potency between cis and trans compounds or between N, N-dimethylamines and primary amines. In the [2.2.1] series the trans exo compounds tended to be least potent against binding, whereas the cis exo compounds were the most potent (4-Cl cis exo: IC50 = 7.7 nM, 27-fold more potent than 4-Cl trans-exo). Although the potencies of the bicyclic derivatives in the binding and uptake assays were highly correlated, some of the compounds were 5-7-fold less potent at inhibiting [3H]dopamine uptake than [3H]WIN 35,428 binding (for comparison, cocaine has a lower discrimination ratio (DR) of 2.5). The DR values were higher for almost all primary amines and for the trans-[2.2.2] series as compared to the cis-[2.2.2]. Most of the compounds had Hill coefficients approaching unity, except for the [2. 2.2] 3,4-dichloro derivatives, which all had nH values of about 2.0. Two of the compounds were shown to fully substitute for cocaine in drug discrimination tests in rats, and one had a very long duration of action.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical | |
pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0022-2623
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
11
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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 |
882-95
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:10072685-Animals,
pubmed-meshheading:10072685-Bicyclo Compounds,
pubmed-meshheading:10072685-Cocaine,
pubmed-meshheading:10072685-Cocaine-Related Disorders,
pubmed-meshheading:10072685-Discrimination Learning,
pubmed-meshheading:10072685-Dopamine,
pubmed-meshheading:10072685-Dopamine Uptake Inhibitors,
pubmed-meshheading:10072685-Male,
pubmed-meshheading:10072685-Models, Molecular,
pubmed-meshheading:10072685-Neostriatum,
pubmed-meshheading:10072685-Protein Binding,
pubmed-meshheading:10072685-Rats,
pubmed-meshheading:10072685-Rats, Sprague-Dawley,
pubmed-meshheading:10072685-Stereoisomerism,
pubmed-meshheading:10072685-Structure-Activity Relationship,
pubmed-meshheading:10072685-Synaptosomes
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pubmed:year |
1999
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pubmed:articleTitle |
Synthesis and pharmacology of site-specific cocaine abuse treatment agents: 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane dopamine uptake inhibitors.
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pubmed:affiliation |
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, USA.
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pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, U.S. Gov't, P.H.S.
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