[3H] A-369508 ([2-[4-(2-cyanophenyl)-1-piperazinyl]-N-(3-methylphenyl) acetamide): an agonist radioligand selective for the dopamine D4 receptor.
Tritiation of the dopamine D(4) receptor selective agonist A-369508 ([2-[4-(2-cyanophenyl)-1-piperazinyl]-N-(3-methylphenyl) acetamide) has provided a radioligand for the characterization of dopamine D(4) receptors. [(3)H] A-369508 binds with high affinity to the major human dopamine D(4) receptor variants D(4.2), D(4.4) and D(4.7) (K(d)=1.7, 4, and 1.2 nM, respectively). It also binds to the rat dopamine D(4) receptor, (K(d)=4.4 nM), implying similar binding affinity across human and rat receptors. A-369508 shows >400-fold selectivity over D(2L), >350-fold selectivity over 5-HT(1A) and >700-1,000-fold selectivity over all other receptors tested. Agonist activity determined by inhibition of forskolin-induced cAMP in Chinese hamster ovary cells transfected with the human dopamine D(4.4) receptor (EC(50)=7.5 nM, intrinsic activity=0.71) indicates that A-369508 is a potent agonist at the human dopamine D(4) receptor. Similar data was observed in other functional assays. [(3)H] A-369508 binds to a single, high affinity site on membranes containing the human dopamine D(4.4) receptor. When compared to the D(2)-like antagonist [(3)H] spiperone, competition binding for agonists like dopamine and apomorphine were 2-10-fold more potent with [(3)H] A-369508, while the antagonists clozapine, haloperidol and L-745870 bind with similar affinity to both ligands. Binding to rat brain regions demonstrated that the most abundant area was cerebral cortex (51.2 fmol/mg protein) followed by hypothalamus, hippocampus, striatum and cerebellum. [(3)H] A-369508 is a useful tool to define the localization and physiological role of dopamine D(4) receptors in central nervous system and can facilitate measuring accurate affinities (K(i)) for structure/activity relationship studies designed to identify dopamine D(4) receptor selective agonists.
Neuroscience Research Global Pharmaceutical Research and Development, AP9 Room 1125, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6118, USA.
Robert B
RB
Moreland
Marc A
MA
Terranova
Renjie
R
Chang
Marie E
ME
Uchic
Mark A
MA
Matulenko
Bruce W
BW
Surber
Andrew O
AO
Stewart
Jorge D
JD
Brioni
D000081:Acetamides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D018491:Dopamine Agonists / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism; D011869:Radioligand Assay / Q000379:methods*; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism*; D050638:Receptors, Dopamine D4; D014316:Tritium
C497465:2-(4-(2-cyanophenyl)-1-piperazinyl)-N-(3-methylphenyl) acetamide; D000081:Acetamides; C493599:DRD4 protein, human; D018491:Dopamine Agonists; C493601:Drd4 protein, rat; D008024:Ligands; D010879:Piperazines; D017448:Receptors, Dopamine D2; D014316:Tritium; D050638:Receptors, Dopamine D4