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

A series of 2-(2,3-dimethoxyphenyl)-4-(aminomethyl)imidazole derivatives wa s prepared and their affinity for dopamine D-2 and D-3 receptors was measur ed using in vitro binding assays. Several oxadiazole analogues were also pr epared and tested for their affinity for dopamine D-2 and D-3 receptors. Th e results of receptor binding studies indicated that the incorporation of a ll 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 l oss 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 a lso measured, and the results showed that several analogues were selective sigma (1) receptor ligands. (C) 2001 Elsevier Science Ltd. All rights reser ved.