KW-3902, a selective high affinity antagonist for adenosine A_1 receptors

摘要

1 We demonstrate that 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902) is a very potent and selective adenosine A_1 receptor antagonist, assessed by radioligand binding and cyclic AMP response in cells. 2 In rat forebrain adenosine A, receptors labelled with [~3H]-cyclohexyladenosine (CHA), KW-3902 had a K_i value of 0.19 nM, whereas it showed a K_i value of 170 nM in rat striatal A_2A receptors labelled with [~3H]-2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680), indicating 890 fold A_1 receptor selectivity versus the A_2A receptor. KW-3902 at 10 μM showed no effect on recombinant rat A_3 receptors expressed on CHO cells. 3 Saturation studies with [~3H]-KW-3902 revealed that it bound with high affinity (K_d = 77 pM) and limited capacity (B_(max) = 470 fmol mg~(-1) of protein) to a single class of recognition sites. A high positive correlation was observed between the pharmacological profile of adenosine ligands inhibiting the binding of [~3H]-KW-3902 and that of [~3H]-CHA. 4 KW-3902 showed potent A_1 antagonism against the inhibition of forskolin-induced cyclic AMP accumulation in DDT1 MF-2 cells by the A_1-selective agonist, cyclopentyladenosine with a dissociation constant (K_B value) of 0.34 nM. KW-3902 antagonized 5'-N-ethylcarboxamidoadenosine-elicited cyclic AMP accumulation via A_(2B) receptors with a K_B value of 52 nM. 5 KW-3902 exhibited marked species-dependent differences in the binding affinities. The highest affinity was for the rat A_1 receptor (K_i = 0.19 nM) and these values for guinea-pig and dog A_1 receptors were 1.3 and 10 nM, respectively.