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Vol. 281, Issue 2, 761-768, 1997
Departments of
Medicine (C.A.K.-B., J.R., J.S., L.B.) and
Pharmacology (J.K.H., M.O., L.B.), University of Florida, Gainesville,
Florida and
Merck Research Laboratories, West Point, Pennsylvania
(M.J.)
The allosteric enhancer PD 81,723, a 2-amino-3-benzoylthiophene
derivative, has been shown to potentiate agonist binding to A1 adenosine receptors (A1AdoRs) and to enhance
the functional effects of adenosine and adenosine analogs. The
objective of this study was to determine whether the apparent
agonist-independent effect of PD 81,723 observed in CHO cells stably
expressing the recombinant human A1AdoR was due to the
potentiation of the action of endogenous adenosine, to the presence of
constitutive receptor activity and/or to the binding of PD 81,723 to
the agonist binding site of the A1AdoR. The allosteric
enhancer PD 81,723, the A1AdoR agonist
(R)-N6-(2-phenylisopropyl)adenosine and
adenosine all significantly inhibited forskolin-stimulated cAMP
accumulation in intact cells and increased
[35S]-5
-(
-thio)triphosphate binding to cell
membranes. The effects of adenosine on cAMP formation and
[35S]-5-(-thio)triphosphate binding were attenuated
by adenosine deaminase, but the effects of PD 81,723 were not. In the
presence of ADA, the A1AdoR antagonist
8-cyclopentyl-1,3-dipropylxanthine increased forskolin-stimulated cAMP
accumulation in cells expressing the recombinant human
A1AdoR but not in nontransfected CHO cells. In binding
experiments, the agonist
(R)-N6-(2-phenylisopropyl)adenosine, but not
PD 81,723, significantly displaced the specific binding of the
A1AdoR agonist
[3H]-N6-cyclohexyladenosine and the
antagonist [3H]-8-cyclopentyl-1,3-dipropylxanthine. The
results of this study demonstrate that in CHO cells stably expressing
the recombinant human A1AdoR, the agonist-independent
effect of PD 81,723 is not due to potentiation of the action of
endogenous adenosine or mediated by the binding of the allosteric
enhancer to the agonist binding site of the recombinant human
A1AdoR. It is possible that these effects are due to
potentiation of constitutive receptor activity by PD 81,723.
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