2-[4-(3,4-Dimethylphenyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393), a selective dopamine D4 receptor antagonist

Abstract 2-[4-(3,4-Dimethylphenlyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393) was identified as a potent dopamine D 4 receptor antagonist with excellent receptor selectivity. [ 3 H]-spiperone competition binding assays showed that A-381393 potently bound to membrane from cells expressing recombinant human dopamine D 4.4 receptor ( K i  = 1.5 nM), which was 20-fold higher than that of clozapine ( K i  = 30.4 nM). A-381393 exhibited highly selective binding for the dopamine D 4.4 receptor (>2700-fold) when compared to D 1 , D 2 , D 3 and D 5 dopamine receptors. Furthermore, in comparison to clozapine and L-745870, A-381393 exhibits better receptor selectivity, showing no affinity up to 10 μM for a panel of more than 70 receptors and channels, with the exception of moderate affinity for 5-HT 2A ( K i  = 370 nM). A-381393 potently inhibited the functional activity of agonist-induced GTP-γ-S binding assay and 1 μM dopamine induced-Ca 2+ flux in human dopamine D 4.4 receptor expressing cells, but not in human dopamine D 2L or D 3 receptor cells. In contrast to L-745870, A-381393 did not exhibit any significant intrinsic activity in a D 4.4 receptor. In vivo, A-381393 has good brain penetration after subcutaneous administration. A-381393 inhibited penile erection induced by the selective D 4 agonist PD168077 in conscious rats. Thus, A-381393 is a novel selective D 4 antagonist that will enhance the ability to study dopamine D 4 receptors both in vitro and in vivo.