N-(3-Fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as Selective Dopamine D3 Receptor Ligands: Critical Role of the Carboxamide Linker for D3 Receptor Selectivity

N-(3-Fluoro-4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazine-1-yl)butyl)arylcarboxamides were prepared and evaluated for binding and function at dopamine D3 receptors (D3Rs) and dopamine D2 receptors (D2Rs). In this series, we discovered some of the most D3R selective compounds reported to date (e....

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Published in:Journal of medicinal chemistry 2011-05, Vol.54 (10), p.3581-3594
Main Authors: Banala, Ashwini K, Levy, Benjamin A, Khatri, Sameer S, Furman, Cheryse A, Roof, Rebecca A, Mishra, Yogesh, Griffin, Suzy A, Sibley, David R, Luedtke, Robert R, Newman, Amy Hauck
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Amides - chemistry
Arrestins - chemistry
beta-Arrestins
Binding Sites
Cell Line
Chemistry, Pharmaceutical - methods
Drug Design
Humans
Inhibitory Concentration 50
Kinetics
Ligands
Magnetic Resonance Spectroscopy
Models, Chemical
Piperazines - chemical synthesis
Piperazines - chemistry
Receptors, Dopamine D3 - chemistry
Receptors, Dopamine D3 - metabolism
Recombinant Fusion Proteins - chemistry
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Summary:N-(3-Fluoro-4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazine-1-yl)butyl)arylcarboxamides were prepared and evaluated for binding and function at dopamine D3 receptors (D3Rs) and dopamine D2 receptors (D2Rs). In this series, we discovered some of the most D3R selective compounds reported to date (e.g., 8d and 8j, >1000-fold D3R-selective over D2R). In addition, chimeric receptor studies further identified the second extracellular (E2) loop as an important contributor to D3R binding selectivity. Further, compounds lacking the carbonyl group in the amide linker were synthesized, and while these amine-linked analogues bound with similar affinities to the amides at D2R, this modification dramatically reduced binding affinities at D3R by >100-fold (e.g., D3R K i for 15b = 393 vs for 8j = 2.6 nM), resulting in compounds with significantly reduced D3R selectivity. This study supports a pivotal role for the D3R E2 loop and the carbonyl group in the 4-phenylpiperazine class of compounds and further reveals a point of separation between structure–activity relationships at D3R and D2R.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/jm200288r