[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.
Moreland
Robert B
RB
Neuroscience Research Global Pharmaceutical Research and Development, AP9 Room 1125, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6118, USA.
Terranova
Marc A
MA
Chang
Renjie
R
Uchic
Marie E
ME
Matulenko
Mark A
MA
Surber
Bruce W
BW
Stewart
Andrew O
AO
Brioni
Jorge D
JD
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