Yc. Kim et al., DERIVATIVES OF THE TRIAZOLOQUINAZOLINE ADENOSINE ANTAGONIST (CGS-15943) HAVING HIGH POTENCY AT THE HUMAN A(2B) AND A(3) RECEPTOR SUBTYPES, Journal of medicinal chemistry, 41(15), 1998, pp. 2835-2845
The adenosine antagonist 2-furanyl)[1,2,4]triazolo[1,5-c]quinazolin-5-
amine (CGS 15943) binds nonselectively to human A(1), A(2A), and A(3)
receptors with high affinity. Acylated derivatives and one alkyl deriv
ative of the 5-amino group and other modifications were prepared in an
effort to enhance A(2B) or A(3) subtype potency. In general, distal m
odifications of the N-5-substituent were highly modulatory to potency
and selectivity at adenosine receptors, as determined in radioligand b
inding assays at rat brain A(1) and A(2A) receptors and at recombinant
human A(3) receptors. In Chinese hamster ovary cells stably transfect
ed with human A(2B) receptor cDNA, inhibition of agonist-induced cycli
c AMP production was measured. An N-5-(2-iodophenyl)acetyl derivative
was highly selective for A(2A) receptors. An (R)-N-5-alpha-methyl-(phe
nylacetyl) derivative was the most potent derivative at A(3) receptors
, with a K-i value of 0.36 nM. A bulky N-5-diphenylacetyl derivative,
13, displayed a K-i value of 0.59 nM at human A(3) receptors and was m
oderately selective for that subtype. Thus, a large, nondiscriminating
hydrophobic region occurs in the Ag receptor in proximity to the N-5-
substituent. A series of straight-chain N-5-aminoalkylacyl derivatives
demonstrated that for A(2B) receptors the optimal chain length occurs
with three methylene groups, i.e., the N-5-gamma-aminobutyryl derivat
ive 27 which had a pA(2) value of 8.0 but was not selective for A(2B)
receptors. At A(1), A(2A), and A(3) receptors however the optimum occu
rs with four methylene groups. An N-5-pivaloyl derivative, which was l
ess potent than 27 at A(1), A(2A), and A(3) receptors, retained modera
te potency at A(2B) receptors. A molecular model of the 27-A(2B) recep
tor complex based on the structure of rhodopsin utilizing a ''cross-do
cking'' procedure was developed in order to visualize the environment
of the ligand binding site.