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

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. [H-3]-spiperoie 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 mu M for a panel of more than 70 receptors and channels, with the exception of moderate affinity for 5-HT2A (K-i = 370 nM). A-381393 potently inhibited the functional activity of agonist-induced GTP-gamma-S binding assay and 1 mu M dopamine induced-Ca2+ 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. (c) 2005 Elsevier Ltd. All rights reserved.