Useful pharmacological parameters for G-protein-coupled receptor homodimers obtained from competition experiments. Agonist–antagonist binding modulation

• Published in: Biochemical pharmacology Vol. 78; no. 12; pp. 1456 - 1463
• Main Authors: Casadó, Vicent, Ferrada, Carla, Bonaventura, Jordi, Gracia, Eduard, Mallol, Josefa, Canela, Enric I., Lluís, Carmen, Cortés, Antoni, Franco, Rafael
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 15-12-2009; Elsevier; Elsevier B.V
• Subjects: Adenosine - analogs & derivatives; Adenosine - pharmacology; Adenosine receptors; Animals; Benzazepines - pharmacology; Binding, Competitive - drug effects; Biochemistry; Biologia molecular; Biological and medical sciences; Bioquímica; Cell interaction; Competition curves; Cooperativity; Dopamine Agonists - pharmacology; Dopamine receptors; Drug Discovery - methods; Equilibrium dissociation constants; Interacció cel·lular; Medical sciences; Models, Biological; Molecular biology; Pharmacology. Drug treatments; Phenethylamines - pharmacology; Radioligand Assay; Receptor, Adenosine A2A - drug effects; Receptors, Dopamine D1 - drug effects; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - drug effects; Sheep; Two-state dimer receptor model; Competition curves; Adenosine receptors; Equilibrium dissociation constants; Cooperativity; Dopamine receptors; Two-state dimer receptor model; Competition; Dopamine receptor; Curve; Equilibrium; G protein coupled receptor; Modulation; Dimer; Models; Adenosine receptor; Agonist antagonist; Biological receptor
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2009.07.012

Dimer receptor models can account for changes in the shape of competition curves that cannot be explained by monomer receptor models. Radiolabelled antagonist versus agonist binding to dopamine D
1 receptors.
Many G-protein-coupled receptors (GPCRs) are expressed on the plasma membrane as dimers. Since drug binding data are currently fitted using equations developed for monomeric receptors, the interpretation of the pharmacological data are equivocal in many cases. As reported here, GPCR dimer models account for changes in competition curve shape as a function of the radioligand concentration used, something that cannot be explained by monomeric receptor models. Macroscopic equilibrium dissociation constants for the agonist and homotropic cooperativity index reflecting the intramolecular communication within the dopamine D
1 or adenosine A
2A receptor homodimer as well as hybrid equilibrium dissociation constant, which reflects the antagonist/agonist modulation may be calculated by fitting binding data from antagonist/agonist competition experiments to equations developed from dimer receptor models. Comparing fitting the data by assuming a classical monomeric receptor model or a dimer model, it is shown that dimer receptor models provide more clues useful in drug discovery than monomer-based models.