Neuroscience 2002 Abstract
| Presentation Number: | 894.5 |
|---|---|
| Abstract Title: | IN VITRO CHARACTERIZATION OF THE SELECTIVE DOPAMINE D3 RECEPTOR ANTAGONIST A-437203. |
| Authors: |
Unger, L.*1
; Garcia-Ladona, F. J.1
; Wernet, W.1
; Sokoloff, P.2
; Wicke, K. M.1
; Gross, G.1
1Abbott GmbH & Co KG, 67008 Ludwigshafen, Germany 2INSERM , Paris, France |
| Primary Theme and Topics |
Neurological and Psychiatric Conditions - Psychiatric Disorders -- Schizophrenia |
| Session: |
894. Psychiatric disorders: schizophrenia--antipsychotic drug actions III Poster |
| Presentation Time: | Thursday, November 7, 2002 8:00 AM-9:00 AM |
| Location: | Hall A2-B3 Y-37 |
| Keywords: | RECEPTOR BINDING, CAMP, GTP, DOPAMINE RECEPTOR |
Dopamine D3 receptors are expressed in brain areas associated with cognitive and emotional responses, their blockade may mediate antipsychotic and other therapeutic effects. We characterized binding and functional properties of A-437203 (previously known as BSF 201640; 2-(3-[4-(2-tert-butyl-6-trifluoromethyl-pyrimidin-4-yl)-piperazin-1-yl]-propyl-sulfanyl)-3H-pyrimidin-4-one fumarate), a new highly potent dopamine D3 receptor ligand.
Binding experiments were performed with the agonist 125I-PIPAT and the antagonists 125I-iodosulpride and 125I-iodospiperone on HEK 293 cells expressing human recombinant dopamine D3, D2L and D2S receptors. Ki values of A-437203 for D3 agonist and antagonist binding sites were 1.6 and 2.9 nM, respectively. The D3 selectivity determined by antagonist binding was 45-fold (D3/D2S) and 120-fold (D3/D2L). No biologically relevant binding of A-437203 to more than 100 other receptors and binding sites was revealed.
Functional properties of A-437203 were assessed in cellular systems with stably transfected human D3 receptors: 1) cAMP-dependent luciferase activity in HEK 293 cells, 2) mitogenic response in NG108-15 neuroblastoma-glioma cells, and 3) stimulation of 35S-GTPγS-binding in CHO cells. In these assays A-437203 was devoid of intrinsic activity but antagonized agonist-induced effects with pK values between 9 and 7.5.
In conclusion, A-437203 is a potent and selective D3 receptor antagonist and thus suited to investigate the physiological role(s) of D3 receptor antagonists.
γ.
Binding experiments were performed with the agonist 125I-PIPAT and the antagonists 125I-iodosulpride and 125I-iodospiperone on HEK 293 cells expressing human recombinant dopamine D3, D2L and D2S receptors. Ki values of A-437203 for D3 agonist and antagonist binding sites were 1.6 and 2.9 nM, respectively. The D3 selectivity determined by antagonist binding was 45-fold (D3/D2S) and 120-fold (D3/D2L). No biologically relevant binding of A-437203 to more than 100 other receptors and binding sites was revealed.
Functional properties of A-437203 were assessed in cellular systems with stably transfected human D3 receptors: 1) cAMP-dependent luciferase activity in HEK 293 cells, 2) mitogenic response in NG108-15 neuroblastoma-glioma cells, and 3) stimulation of 35S-GTPγS-binding in CHO cells. In these assays A-437203 was devoid of intrinsic activity but antagonized agonist-induced effects with pK values between 9 and 7.5.
In conclusion, A-437203 is a potent and selective D3 receptor antagonist and thus suited to investigate the physiological role(s) of D3 receptor antagonists.
γ.
Sample Citation:
[Authors]. [Abstract Title]. Program No. XXX.XX. 2002 Neuroscience Meeting Planner. Orlando, FL: Society for Neuroscience, 2002. Online.
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