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Mechanisms of inverse agonist action at D-2 dopamine receptors

Roberts, D.J. and Strange, P.G. (2005) Mechanisms of inverse agonist action at D-2 dopamine receptors. British Journal of Pharmacology, 145 (1). pp. 34-42. ISSN 0007-1188

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To link to this item DOI: 10.1038/sj.bjp.0706073


1 Mechanisms of inverse agonist action at the D-2(short) dopamine receptor have been examined. 2 Discrimination of G-protein-coupled and -uncoupled forms of the receptor by inverse agonists was examined in competition ligand-binding studies versus the agonist [H-3]NPA at a concentration labelling both G-protein-coupled and -uncoupled receptors. 3 Competition of inverse agonists versus [H-3] NPA gave data that were fitted best by a two-binding site model in the absence of GTP but by a one-binding site model in the presence of GTP. K-i values were derived from the competition data for binding of the inverse agonists to G-protein-uncoupled and -coupled receptors. K-coupled and K-uncoupled were statistically different for the set of compounds tested ( ANOVA) but the individual values were different in a post hoc test only for (+)-butaclamol. 4 These observations were supported by simulations of these competition experiments according to the extended ternary complex model. 5 Inverse agonist efficacy of the ligands was assessed from their ability to reduce agonist-independent [S-35]GTPγ S binding to varying degrees in concentration-response curves. Inverse agonism by (+)-butaclamol and spiperone occurred at higher potency when GDP was added to assays, whereas the potency of (-)-sulpiride was unaffected. 6 These data show that some inverse agonists ((+)-butaclamol, spiperone) achieve inverse agonism by stabilising the uncoupled form of the receptor at the expense of the coupled form. For other compounds tested, we were unable to define the mechanism.

Item Type:Article
Divisions:Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy
ID Code:13648
Uncontrolled Keywords:inverse agonism, mechanism, ligand binding, [S-35] GTP gamma S binding, receptor/G-protein interaction , PROTEIN-COUPLED RECEPTORS, ANTIPSYCHOTIC-DRUGS, CONSTITUTIVE ACTIVITY, LIGAND-BINDING, ACTIVATION, EFFICACY, ANTAGONISM, AFFINITY, MODEL, STATE

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