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.
Nakane
Masaki
M
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. masaki.nakane@abbott.com
Cowart
Marlon D
MD
Hsieh
Gin C
GC
Miller
Loan
L
Uchic
Marie E
ME
Chang
Renjie
R
Terranova
Marc A
MA
Donnelly-Roberts
Diana L
DL
Namovic
Marian T
MT
Miller
Thomas R
TR
Wetter
Jill M
JM
Marsh
Kennan
K
Stewart
Andrew O
AO
Brioni
Jorge D
JD
Moreland
Robert B
RB
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