Synthesis of 2-(2,3-dimethoxyphenyl)-4-(aminomethyl)imidazole analogues and their binding affinities for dopamine D2 and D3 receptors

A series of 2-(2,3-dimethoxyphenyl)-4-(aminomethyl)imidazole derivatives was prepared and their affinity for dopamine D-2 and D-3 receptors was measured using in vitro binding assays. Several oxadiazole analogues were also prepared and tested for their affinity for dopamine D-2 and D-3 receptors. The results of receptor binding studies indicated that the incorporation of all imidazole moiety between the phenyl ring and the basic nitrogen did not significantly increase the selectivity for dopamine D-3 receptors. whereas the incorporation of an oxadiazole at the same region resulted in a total loss of affinity for both dopamine receptor subtype binding sites. The most selective compound in this series is 2-(5-bromo-2,3-dimethoxyphenyl)-4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinomethyl)imidazole (5i). which has a D-3 receptor affinity of 21 nM and a 7-fold selectivity for D-3 versus D-2 receptors. The binding affinity or sigma (1) and sigma (2) receptors was also measured, and the results showed that several analogues were selective sigma (1) receptor ligands. (C) 2001 Elsevier Science Ltd. All rights reserved.