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Allosteric modulation of the rat adenosine A 1 receptor: Differential effects on agonist and antagonist binding
Author(s) -
Kourounakis Angeliki P.,
Visser Corine,
de Groote Miriam,
IJzerman Ad P.
Publication year - 2000
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.1
Subject(s) - agonist , chemistry , allosteric regulation , partial agonist , adenosine , inverse agonist , gtp' , adenosine receptor , suramin , antagonist , receptor , adenosine a1 receptor , allosteric modulator , intrinsic activity , adenosine a2b receptor , biophysics , pharmacology , medicine , biochemistry , biology , enzyme
The interaction of 2‐amino‐3‐benzoyl‐thiophene derivative, PD81,723, as well as other G protein‐coupled receptor (GPCR)‐modulating agents such as suramin (SUR), N‐ethylmaleimide (NEM), GTP, and NaCl with the rat adenosine A 1 receptor was investigated using kinetic, saturation, as well as displacement experiments of various agonists, partial agonists or antagonists. PD81,723 enhanced agonist (CPA, R‐PIA, NECA) binding ∼2‐fold, while its effect on CPA binding was increased (4–11‐fold) with other modulators present. In contrast, binding of antagonists (DPCPX, CPT, N‐0840) was inhibited, while binding of partial agonists (8BCPA, MeSCPA) remained uninfluenced. The effect of PD81,723 is consistent with shifting A 1 receptors to an “active” (R*) state with high affinity for agonists and low for antagonists. Further, all described allosteric modulators influenced both agonist and antagonist binding. The IC 50 values observed for the agonist CPA, ranging from 4.7 nM in the presence of PD81,723 to a high value of 2.9 μM in the combined presence of NEM, NaCl, and GTP, represented a greater than 600‐fold affinity shift. We suggest that the latter micromolar IC 50 value may approximate CPA’s “true” affinity (K A ) for the rat adenosine A 1 receptor. Drug Dev. Res. 51:207–215, 2000. © 2001 Wiley‐Liss, Inc.