Abstract
An enlarged series of pyrazolotriazolopyrimidines previously reported,
in preliminary form (Baraldi et al. J. Med. Chem. 1999, 42, 4473-4478),
as highly potent and selective human A(3) adenosine receptor antagonists
is described. The synthesized compounds showed A(3) adenosine receptor
affinity in the sub-nanomolar range and high levels of selectivity
evaluated in radioligand binding assays at human A(1), A(2A), A(2B),
and A(3) adenosine receptors. In particular, the effect of the chain
at the N(8) pyrazole nitrogen was analyzed. This study allowed us
to identify the derivative with the methyl group at the N(8) pyrazole
combined with the 4-methoxyphenylcarbamoyl moiety at the N(5) position
as the compound with the best binding profile in terms of both affinity
and selectivity (hA(3) = 0.2 nM, hA(1)/hA(3) = 5485, hA(2A)/hA(3)
= 6950, hA(2B)/hA(3) = 1305). All the compounds proved to be full
antagonists in a specific functional model where the inhibition of
cAMP generation by IB-MECA was measured in membranes of CHO cells
stably transfected with the human A(3) receptor. The new compounds
are among the most potent and selective A(3) antagonists so far described.
The derivatives with higher affinity at human A(3) adenosine receptors
proved to be antagonists, in the cAMP assay, capable of inhibiting
the effect of IB-MECA with IC(50) values in the nanomolar range,
with a trend strictly similar to that observed in the binding assay.
Also a molecular modeling study was carried out, with the aim to
identify possible pharmacophore maps. In fact, a sterically controlled
structure-activity relationship was found for the N(8) pyrazole substituted
derivatives, showing a correlation between the calculated molecular
volume of pyrazolo4,3-e1,2, 4-triazolo1,5-cpyrimidine derivatives
and their experimental K(i) values.
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