2-[4-(3,4-Dimethylphenyl)piperazin-1-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 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.
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. masaki.nakane@abbott.com
Masaki
M
Nakane
Marlon D
MD
Cowart
Gin C
GC
Hsieh
Loan
L
Miller
Marie E
ME
Uchic
Renjie
R
Chang
Marc A
MA
Terranova
Diana L
DL
Donnelly-Roberts
Marian T
MT
Namovic
Thomas R
TR
Miller
Jill M
JM
Wetter
Kennan
K
Marsh
Andrew O
AO
Stewart
Jorge D
JD
Brioni
Robert B
RB
Moreland
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003024:Clozapine / Q000493:pharmacokinetics; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004347:Drug Interactions; D005063:Europium / Q000493:pharmacokinetics; D005470:Fluorometry / Q000379:methods; D018756:GABA Antagonists / Q000493:pharmacokinetics; D006160:Guanosine Triphosphate / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D010410:Penile Erection / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000493:pharmacokinetics; D011758:Pyrroles / Q000493:pharmacokinetics; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013134:Spiperone / Q000493:pharmacokinetics; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
C505414:2-(4-(3,4-dimethylphenyl)piperazin-1-ylmethyl)-1H-benzimidazole; C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; D001549:Benzamides; D001562:Benzimidazoles; D018492:Dopamine Antagonists; D018756:GABA Antagonists; C477501:N-((4-(2-cyanophenyl)-1-piperazinyl)methyl)-3-methylbenzamide; D010879:Piperazines; D011725:Pyridines; D011758:Pyrroles; D014316:Tritium; D005063:Europium; D013134:Spiperone; D006160:Guanosine Triphosphate; D003024:Clozapine; D002118:Calcium; D004298:Dopamine