Hybrid approach for the design of highly affine and selective dopamine D(3) receptor ligands using privileged scaffolds of biogenic amine GPCR ligands

A series of compounds containing privileged scaffolds of the known histamine H(1) receptor antagonists cetirizine, mianserin, ketotifen, loratadine, and bamipine were synthesized for further optimization as ligands for the related biogenic amine binding dopamine D(3) receptor. A pharmacological scre...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2007-12, Vol.15 (23), p.7258-7273
Main Authors: Sasse, Britta C, Mach, Ulrich R, Leppaenen, Jukka, Calmels, Thierry, Stark, Holger
Format: Article
Language:English
Subjects:
Amines - chemistry
Animals
Binding, Competitive
Cell Line
Cetirizine - chemical synthesis
Cetirizine - chemistry
Cetirizine - pharmacology
CHO Cells
Cricetinae
Cricetulus
Dopamine D2 Receptor Antagonists
Drug Design
Drug Evaluation, Preclinical
Histamine H1 Antagonists - chemical synthesis
Histamine H1 Antagonists - chemistry
Histamine H1 Antagonists - pharmacology
Humans
Ketotifen - chemical synthesis
Ketotifen - chemistry
Ketotifen - pharmacology
Ligands
Loratadine - chemical synthesis
Loratadine - chemistry
Loratadine - pharmacology
Mianserin - chemical synthesis
Mianserin - chemistry
Mianserin - pharmacology
Molecular Structure
Piperidines - chemical synthesis
Piperidines - chemistry
Piperidines - pharmacology
Receptors, Dopamine D3 - antagonists & inhibitors
Stereoisomerism
Structure-Activity Relationship
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Summary:A series of compounds containing privileged scaffolds of the known histamine H(1) receptor antagonists cetirizine, mianserin, ketotifen, loratadine, and bamipine were synthesized for further optimization as ligands for the related biogenic amine binding dopamine D(3) receptor. A pharmacological screening was carried out at dopamine D(2) and D(3) receptors. In the preliminary testing various ligands have shown moderate to high affinities for dopamine D(3)receptors, for example, N-(4-{4-[benzyl(phenyl)amino]piperidin-1-yl}butylnaphthalen-2-carboxamide (19a) (hD(3)K(i)=0.3 nM; hD(2)K(i)=703 nM), leading to a selectivity ratio of 2343.
ISSN:0968-0896