Synthesis, dopamine D 2 receptor binding studies and docking analysis of 5-[3-(4-arylpiperazin-1-yl)propyl]-1H-benzimidazole, 5-[2-(4-arylpiperazin-1-yl)ethoxy]-1H-benzimidazole and their analogs

Abstract

5-[3-(4-Arylpiperazin-1-yl)propyl]-1H-benzimidazoles and 5-[2-(4-arylpiperazin-1-yl)ethoxy]-1H-benzimidazoles were synthesized and their affinity for the D 1 , D 2 and 5-HT 1A receptors examined. They expressed a rather high affinity for the D 2 dopamine receptor. The main features of ligand-D 2 receptor interactions revealed by docking analyses were: salt bridge between piperazine ring protonated N 1 and Asp 86, hydrogen bonds of ligand bezimidazole part with Ser 141, Ser 122 and His 189, edge-to-face interactions of arylpiperazine aromatic ring with Phe 178, Tyr 216 and Trp 182 and hydrogen bond between ethereal oxygen in ethylenoxy ligands and hydrogen of Phe 185 or Trp 115. The most active 5-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethoxy}-1,3-dihydro-2H- benzimidazole-2-thione (27) has a maximal number of attractive interactions. A satisfactory correlation between docking of the compounds into the D 2 receptor and competition binding results was observed. © 2005 Elsevier SAS. All rights reserved.