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KW‐3902, a selective high affinity antagonist for adenosine A 1 receptors
Author(s) -
akay Hiromi,
Ichimura Michio,
Takeda Masami,
Kanda Tomoyuki,
Shimada Junichi,
Suzuki Fumio,
Kase Hiroshi
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15335.x
Subject(s) - antagonist , receptor , adenosine receptor , adenosine , chemistry , pharmacology , endocrinology , medicine , biochemistry , biology , agonist
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 1 receptors labelled with [ 3 H]‐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 [ 3 H]‐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 μ m showed no effect on recombinant rat A 3 receptors expressed on CHO cells. 3 Saturation studies with [ 3 H]‐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 [ 3 H]‐KW‐3902 and that of [ 3 H]‐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 Arselective 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.