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Molecular Pharmacology

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Research ArticleArticle

Allosteric Enhancers of A1 Adenosine Receptors Increase Receptor-G Protein Coupling and Counteract Guanine Nucleotide Effects on Agonist Binding

Heidi Figler, Ray A. Olsson and Joel Linden
Molecular Pharmacology December 2003, 64 (6) 1557-1564; DOI: https://doi.org/10.1124/mol.64.6.1557
Heidi Figler
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Ray A. Olsson
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Joel Linden
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Abstract

Endogenous ligands of G protein-coupled receptors bind to orthosteric sites that are topologically distinct from allosteric sites. Certain aminothiophenes such as (2-amino-4,5-dimethyl-3-thienyl)-[3-(trifluromethyl)-phenyl]-methanone (PD81,723) and 2-amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-yl)-biphenyl-4-yl-methanone (ATL525) are positive allosteric regulators, or enhancers, of the human A1 adenosine receptor (A1AR). In equilibrium binding assays, 125I-N6-aminobenzyladenosine (125I-ABA) binds to two affinity states of A1AR with KD-high (0.33 μM) and KD-low (∼10 nM). Enhancers have little effect on KD-high but convert all A1AR binding sites to the high-affinity state. Enhancers decrease the potency of guanosine 5′-O-(3-thio)triphosphate (GTPγS) as an inhibitor of agonist binding by 100-fold and increase agonist-stimulated guanine nucleotide exchange. The association of 125I-ABA to high-affinity receptors on Chinese hamster ovary (CHO)-hA1 membranes does not follow theoretical single-site association kinetics but is approximated by a bi-exponential equation with t1/2 values of 1.85 and 12.8 min. Allosteric enhancers selectively increase the number of slow binding sites, possibly by stabilizing newly formed receptor-G protein complexes. A new rapid assay method scores enhancer activity on a scale from 0 to 100 based on their ability to prevent the rapid dissociation of 125I-ABA from A1AR in response to GTPγS. Compared with PD81,723, ATL525 (100 μM) scores higher (27 versus 79) and has less antagonist activity. ATL525 functionally enhances A1 signaling to inhibit cAMP accumulation in CHO-hA1 cells. These data suggest that simultaneously binding orthosteric and allosteric enhancer ligands convert the A1AR from partly to fully coupled to G proteins and prevents rapid uncoupling upon binding of GTPγS.

  • Received June 25, 2003.
  • Accepted September 11, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 64 (6)
Molecular Pharmacology
Vol. 64, Issue 6
1 Dec 2003
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Research ArticleArticle

Allosteric Enhancers of A1 Adenosine Receptors Increase Receptor-G Protein Coupling and Counteract Guanine Nucleotide Effects on Agonist Binding

Heidi Figler, Ray A. Olsson and Joel Linden
Molecular Pharmacology December 1, 2003, 64 (6) 1557-1564; DOI: https://doi.org/10.1124/mol.64.6.1557

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Research ArticleArticle

Allosteric Enhancers of A1 Adenosine Receptors Increase Receptor-G Protein Coupling and Counteract Guanine Nucleotide Effects on Agonist Binding

Heidi Figler, Ray A. Olsson and Joel Linden
Molecular Pharmacology December 1, 2003, 64 (6) 1557-1564; DOI: https://doi.org/10.1124/mol.64.6.1557
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