Synthesis and in vitro evaluation of 2,3-dimethoxy-5-(fluoroalkyl)-substituted benzamides: high-affinity ligands for CNS dopamine D2 receptors

A number of 2,3-dimethoxy-5-(fluoroalkyl)-N-[(1-ethyl-2- pyrrolidinyl)methyl]benzamides (with or without a 6-hydroxy group) were synthesized and evaluated as dopamine D2 receptor ligands. The parent acids were synthesized via the Claisen rearrangement of the appropriate O-allyl ethers, which were de...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1991-05, Vol.34 (5), p.1612-1624
Main Authors: Bishop, John E, Mathis, Chester A, Gerdes, John M, Whitney, John M, Eaton, Allison M, Mailman, Richard B
Format: Article
Language:English
Subjects:
Animals
Benzamides - chemical synthesis
Benzamides - metabolism
Benzamides - pharmacology
Binding, Competitive
Brain - drug effects
Brain - metabolism
Central Nervous System - drug effects
Central Nervous System - metabolism
Chemical Phenomena
Chemistry
Exact sciences and technology
Ligands
Noncondensed benzenic compounds
Organic chemistry
Preparations and properties
Rats
Rats, Inbred Strains
Receptors, Dopamine - drug effects
Receptors, Dopamine D2
Structure-Activity Relationship
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Summary:A number of 2,3-dimethoxy-5-(fluoroalkyl)-N-[(1-ethyl-2- pyrrolidinyl)methyl]benzamides (with or without a 6-hydroxy group) were synthesized and evaluated as dopamine D2 receptor ligands. The parent acids were synthesized via the Claisen rearrangement of the appropriate O-allyl ethers, which were derived from o-vanillic acid or 2,3-dimethoxysalicylic acid. A decrease in reactivity was found to be characteristic of pentasubstituted benzoates, and difficulties were encountered with the introduction of fluorine onto the ethyl side chains. The (fluoroethyl)- and (fluoropropyl)salicylamides were 5 times more potent than the corresponding benzamides in inhibiting [3H]spiperone binding to the D2 receptor. These (fluoroalkyl)salicylamides are of potential value for in vivo positron emission tomography (PET) studies upon the basis of their relatively selective, high potency binding affinity for the D2 receptor.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00109a013