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Assays for enhanced activity of low efficacy partial agonists at the D-2 dopamine receptor

Lin, H., Saisch, S.G.N. and Strange, P.G. (2006) Assays for enhanced activity of low efficacy partial agonists at the D-2 dopamine receptor. British Journal of Pharmacology, 149 (3). pp. 291-299. ISSN 0007-1188

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To link to this item DOI: 10.1038/sj.bjp.0706866


Background and purpose: Low efficacy partial agonists at the D-2 dopamine receptor may be useful for treating schizophrenia. In this report we describe a method for assessing the efficacy of these compounds based on stimulation of [S-35]GTP gamma S binding. Experimental approach: Agonist efficacy was assessed from [S-35]GTP gamma S binding to membranes of CHO cells expressing D2 dopamine receptors in buffers with and without Na+. Effects of Na+ on receptor/G protein coupling were assessed using agonist/[H-3] spiperone competition binding assays. Key results: When [S-35]GTP gamma S binding assays were performed in buffers containing Na+, some agonists (aripiprazole, AJ-76, UH-232) exhibited very low efficacy whereas other agonists exhibited measurable efficacy. When Na+ was substituted by N-methyl D-glucamine, the efficacy of all agonists increased (relative to that of dopamine) but particularly for aripiprazole, aplindore, AJ-76, (-)-3-PPP and UH-232. In ligand binding assays, substitution of Na+ by N-methyl D-glucamine increased receptor/G protein coupling for some agonists -. aplindore, dopamine and (-)-3-PPP-but for aripiprazole, AJ-76 and UH-232 there was little effect on receptor/G protein coupling. Conclusions and implications: Substitution of Na+ by NMDG increases sensitivity in [S-35] GTPgS binding assays so that very low efficacy agonists were detected clearly. For some agonists the effect seems to be mediated via enhanced receptor/G protein coupling whereas for others the effect is mediated at another point in the G protein activation cycle. AJ-76, aripiprazole and UH-232 seem particularly sensitive to this change in assay conditions. This work provides a new method to discover these very low efficacy agonists.

Item Type:Article
Divisions:Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy
ID Code:13701
Uncontrolled Keywords:D-2 dopamine receptor, [S-35]GTP gamma S binding, ligand binding, signalling efficacy, sodium ions, LIGAND-BINDING, INVERSE AGONISM, AUTORECEPTOR ANTAGONISTS, SCHIZOAFFECTIVE DISORDER, RAT THALAMUS, ARIPIPRAZOLE, MECHANISMS, SCHIZOPHRENIA, CELLS, D-2(LONG)

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