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Vol. 53, Issue 5, 886-893, May 1998
Departments of
Medicine (J.C.S., L.B.) and
Pharmacology (M.J.O.,
L.B.), University of Florida, Gainesville, Florida 32610
Receptor antagonists can be classified as neutral antagonists or
antagonists with inverse agonist activity based on their effectiveness
to reduce the spontaneous agonist-independent activity of receptors.
The goals of this study were to (1) demonstrate that
A1-adenosine receptors (A1AdoRs) expressed at
high density (4000-8000 fmol/mg of protein) in Chinese hamster ovary
(CHO) cells cause constitutive activation of inhibitory G proteins and inhibition of adenylyl cyclase activity and (2) identify both neutral
A1AdoR antagonists and antagonists with inverse agonist activity. The activity of A1AdoR agonists and antagonists
was determined by assays of both specific binding of
[35S]guanosine-5'-O-(3-thio)triphosphate
([35S]GTP
S) to membranes and cAMP content of intact
cells in the presence of adenosine deaminase (2-5 units/ml). The
A1AdoR agonist N6-cyclopentyladenosine (CPA)
significantly increased binding of [35S]GTPS by
241 ± 7% compared with control. The A1AdoR
antagonists N-0861, N-0840, and WRC-0342 did not alter binding of
[35S]GTPS, whereas the antagonists
8-cyclopentyl-1,3-dipropylxanthine (CPX), CGS-15943, xanthine amine
congener, and WRC-0571 significantly reduced binding of
[35S]GTPS by 28-53% from control, respectively. The
effects of both the agonist N6-cyclopentyladenosine (CPA)
and the antagonist CPX to alter binding of [35S]GTPS
were attenuated by 1 µM N-0861. CPA reduced cAMP content of forskolin-stimulated CHO:A1AdoR cells, and N-0861 and
WRC-0342 did not alter cAMP content, but the antagonists CPX and
WRC-0571 increased the cAMP content of CHO:A1AdoR cells.
The effects of both CPX and WRC-0571 to increase cAMP content of
forskolin-stimulated CHO:A1AdoR cells were attenuated by
either N-0861 or WRC-0342. The results indicate that both N-0861 and
WRC-0342 are neutral antagonists, whereas both CPX and WRC-0571 are
antagonists with inverse agonist activity.
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