Synthesis of 3-(3-hydroxyphenyl)pyrrolidine dopamine D3 receptor ligands with extended functionality for probing the secondary binding pocket

[Display omitted] A series of 3-(3-hydroxyphenyl)pyrrolidine analogues which incorporate N-alkyl groups and N-butylamide-linked benzamide functionality have been synthesized and their in vitro binding affinities at human dopamine receptors have been evaluated. Our ligand design strategy was to take...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2018-06, Vol.28 (10), p.1897-1902
Main Authors: Omran, Anahid, Eslamimehr, Shakiba, Crider, A. Michael, Neumann, William L.
Format: Article
Language:English
Subjects:
D3 secondary binding pocket
Dopamine D3 receptor selectivity
Dopamine receptors
Homologous series
Structure-activity relationships
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Summary:[Display omitted] A series of 3-(3-hydroxyphenyl)pyrrolidine analogues which incorporate N-alkyl groups and N-butylamide-linked benzamide functionality have been synthesized and their in vitro binding affinities at human dopamine receptors have been evaluated. Our ligand design strategy was to take the 3-(3-hydroxyphenyl)pyrrolidine scaffold and extend functionality from the orthosteric binding site to the secondary binding pocket for enhancing affinity and selectivity for the D3 receptor. The N-alkyl analogues constitute a homologous series from N-pentyl to N-decyl to probe the length/bulk tolerance of the secondary binding pocket of the D3 receptor. Enantiomeric 3-(3-hydroxyphenyl)pyrrolidine analogues were also prepared in order to test the chirality preference of the orthosteric binding site for this scaffold. Benzamide analogues were prepared to enhance affinity and/or selectivity based upon the results of the homologous series.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2018.03.084