210991-27-8Relevant articles and documents
Derivatives of the triazoloquinazoline adenosine antagonist (CGS 15943) having high potency at the human A(2B) and A3 receptor subtypes
Kim, Yong-Chul,De Zwart, Maarten,Chang, Louis,Moro, Stefano,Von Frijtag Drabbe Künzel, Jacobien K.,Melman, Neli,IJzerman, Ad P.,Jacobson, Kenneth A.
, p. 2835 - 2845 (1998)
The adenosine antagonist 9-chloro-2-(2-furanyl)[1,2,4]triazolo[1,5- c]quinazolin-5-amine (CGS 15943) binds nonselectively to human A1, A(2A), and A3 receptors with high affinity. Acylated derivatives and one alkyl derivative of the 5-amino group and other modifications were prepared in an effort to enhance A(2B) or A3 subtype potency. In general, distal modifications of the N5substituent were highly modulatory to potency and selectivity at adenosine receptors, as determined in radioligand binding assays at rat brain A1 and A(2A) receptors and at recombinant human A3 receptors. In Chinese hamster ovary cells stably transfected with human A(2B) receptor cDNA, inhibition of agonist-induced cyclic AMP production was measured. An N5-(2iodophenyl)acetyl derivative was highly selective for A(2A) receptors. An (R)-N5-α-methyl(phenylacetyl) derivative was the most potent derivative at A3 receptors, with a K(i) value of 0.36 nM. A bulky N5-diphenylacetyl derivative, 13, displayed a K(i) value of 0.59 nM at human A3 receptors and was moderately selective for that subtype. Thus, a large, nondiscriminating hydrophobic region occurs in the A3 receptor in proximity to the N5-substituent. A series of straight-chain N5-aminoalkylacyl derivatives demonstrated that for A(2B) receptors the optimal chain length occurs with three methylene groups, i.e., the N5-γ-aminobutyryl derivative 27 which had a pA2 value of 8.0 but was not selective for A(2B) receptors. At A1, A(2A), and A3 receptors however the optimum occurs with four methylene groups. An N5-pivaloyl derivative, which was less potent than 27 at A1, A(2A), and A3 receptors, retained moderate potency at A(2B) receptors. A molecular model of the 27-A(2B) receptor complex based on the structure of rhodopsin utilizing a 'cross-docking' procedure was developed in order to visualize the environment of the ligand binding site.
