Hybrid approach for the design of highly affine and selective dopamine D3 receptor ligands using privileged scaffolds of biogenic amine GPCR ligands

A series of compounds containing privileged scaffolds of the known histamine H1 receptor antagonists cetirizine, mianserin, ketotifen, loratadine, and bamipine were synthesized for further optimization as ligands for the related biogenic amine binding dopamine D3 receptor. A pharmacological screening was carried out at dopamine D2 and D3 receptors. In the preliminary testing various ligands have shown moderate to high affinities for dopamine D3receptors, for example, N-(4-{4-[benzyl(phenyl)amino]piperidin-1-yl}butylnaphthalen-2-carboxamide (19a) (hD3Ki = 0.3 nM; hD2Ki = 703 nM), leading to a selectivity ratio of 2343.

The design and optimization of dopamine D3 receptor ligands has been performed applying a hybrid structure development. Novel ligands were synthesized containing privileged scaffolds of known histamine H1 receptor antagonists and fragments of dopamine D3 receptor-preferring ligands. Compounds were screened in vitro for binding affinities at dopamine D2 and D3 receptors, recognizing the most promising compound with a Ki (hD3) = 0.3 nM and a selectivity ratio of 2343.Figure optionsDownload as PowerPoint slide