title: Aplindore (DAB-452), a high affinity selective dopamine D2 receptor partial agonist.
abstract: The pharmacology of aplindore (DAB-452) was characterized in CHO-K1 cells stably transfected with the human dopamine D(2) receptor short isoform (CHO-D(2s)) and in a behavioral model for post-synaptic agonism in rats. In [(3)H]-spiperone competition binding studies, aplindore showed high affinity for dopamine D(2) and D(3) receptors and low affinity for the dopamine D(4), serotonin (5-HT)(1A), 5-HT(2) receptors and the alpha1-adrenoceptor. The high potency partial agonist activity of aplindore was demonstrated in [(35)S]guanosine 5'-O-(3-thiotriphosphate) ([(35)S]GTPgammaS) binding, extracellular signal-regulated kinase (ERK)-phosphorylation and intracellular calcium flux assay using fluorometric plate reader ([Ca(2+)](i)-FLIPR) format. The [Ca(2+)](i)-FLIPR assay was conducted with CHO-D(2S) receptor cells also stably expressing chimeric G(alphaq/o)-proteins. In all assay modalities, the potencies and intrinsic activities of aplindore were lower than dopamine and higher than aripiprazole. In contrast to the [(35)S]GTPgammaS binding and ERK-phosphorylation assays, the [Ca(2+)](i)-FLIPR assay was able to detect the low partial agonist activity of SDZ 208-912. In unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, aplindore induced contralateral turning, which was blocked by the dopamine D(2) receptor antagonist raclopride. The dopamine D(2) receptor selective partial agonist profile of aplindore suggests that it should be effective for the treatment of dopaminergic-based disorders, such as schizophrenia and Parkinson's disease.
authors.affiliation: Discovery Neuroscience, Wyeth Research, CN8000, Princeton, NJ 08543-8000, USA. heinrij@wyeth.com
authors.forename: Julia N
authors.initials: JN
authors.lastname: Heinrich
authors.forename: Julie
authors.initials: J
authors.lastname: Brennan
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Lai
authors.forename: Kelly
authors.initials: K
authors.lastname: Sullivan
authors.forename: Geoff
authors.initials: G
authors.lastname: Hornby
authors.forename: Mike
authors.initials: M
authors.lastname: Popiolek
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Jiang
authors.forename: Mark H
authors.initials: MH
authors.lastname: Pausch
authors.forename: Gary
authors.initials: G
authors.lastname: Stack
authors.forename: Karen L
authors.initials: KL
authors.lastname: Marquis
authors.forename: Terrance H
authors.initials: TH
authors.lastname: Andree
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D018491:Dopamine Agonists / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D019257:Quinpirole / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D050638:Receptors, Dopamine D4 / Q000378:metabolism; D044348:Receptors, Serotonin, 5-HT2 / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology
chemical_list: D018491:Dopamine Agonists; D044385:GTP-Binding Protein alpha Subunits; D007211:Indoles; D018340:Receptors, Adrenergic, alpha-1; D017448:Receptors, Dopamine D2; D044348:Receptors, Serotonin, 5-HT2; D044282:Receptor, Serotonin, 5-HT1A; D050638:Receptors, Dopamine D4; C515853:aplindore fumarate; D019257:Quinpirole; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D016627:Oxidopamine; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium