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

• Published in: Neuropharmacology 2005-07, Vol.49 (1), p.112-121
• Main Authors: Nakane, Masaki, Cowart, Marlon D, Hsieh, Gin C, Miller, Loan, Uchic, Marie E, Chang, Renjie, Terranova, Marc A, Donnelly-Roberts, Diana L, Namovic, Marian T, Miller, Thomas R, Wetter, Jill M, Marsh, Kennan, Stewart, Andrew O, Brioni, Jorge D, Moreland, Robert B
• Format: Article
• Language: English
• Subjects: Animals; Benzamides - pharmacology; Benzimidazoles - chemical synthesis; Benzimidazoles - pharmacokinetics; Benzimidazoles - pharmacology; Binding, Competitive - drug effects; Calcium - metabolism; Cell Line; Clozapine - pharmacokinetics; Dopamine - metabolism; Dopamine Antagonists - chemical synthesis; Dopamine Antagonists - chemistry; Dopamine Antagonists - pharmacology; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; Europium - pharmacokinetics; Fluorometry - methods; GABA Antagonists - pharmacokinetics; Guanosine Triphosphate - pharmacokinetics; Humans; Male; Penile Erection - drug effects; Piperazines - chemical synthesis; Piperazines - pharmacokinetics; Piperazines - pharmacology; Pyridines - pharmacokinetics; Pyrroles - pharmacokinetics; Radioligand Assay - methods; Rats; Rats, Sprague-Dawley; Rats, Wistar; Spiperone - pharmacokinetics; Time Factors; Tritium - pharmacokinetics
• ISSN: 0028-3908
• DOI: 10.1016/j.neuropharm.2005.02.004

2-[4-(3,4-Dimethylphenlyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393) was identified as a potent dopamine D4 receptor antagonist with excellent receptor selectivity. [3H]-spiperone competition binding assays showed that A-381393 potently bound to membrane from cells expressing recombinant human dopamine D4.4 receptor (Ki=1.5 nM), which was 20-fold higher than that of clozapine (Ki=30.4 nM). A-381393 exhibited highly selective binding for the dopamine D4.4 receptor (>2700-fold) when compared to D1, D2, D3 and D5 dopamine receptors. Furthermore, in comparison to clozapine and L-745870, A-381393 exhibits better receptor selectivity, showing no affinity up to 10 microM for a panel of more than 70 receptors and channels, with the exception of moderate affinity for 5-HT2A (Ki=370 nM). A-381393 potently inhibited the functional activity of agonist-induced GTP-gamma-S binding assay and 1 microM dopamine induced-Ca2+ flux in human dopamine D4.4 receptor expressing cells, but not in human dopamine D2L or D3 receptor cells. In contrast to L-745870, A-381393 did not exhibit any significant intrinsic activity in a D4.4 receptor. In vivo, A-381393 has good brain penetration after subcutaneous administration. A-381393 inhibited penile erection induced by the selective D4 agonist PD168077 in conscious rats. Thus, A-381393 is a novel selective D4 antagonist that will enhance the ability to study dopamine D4 receptors both in vitro and in vivo.