title: KW-3902, a selective high affinity antagonist for adenosine A1 receptors.
abstract: 1. We demonstrate that 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902) is a very potent and selective adenosine A1 receptor antagonist, assessed by radioligand binding and cyclic AMP response in cells. 2. In rat forebrain adenosine A1 receptors labelled with [3H]-cyclohexyladenosine (CHA), KW-3902 had a Ki value of 0.19 nM, whereas it showed a Ki value of 170 nM in rat striatal A2A receptors labelled with [3H]-2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoad enosine (CGS21680), indicating 890 fold A1 receptor selectivity versus the A2A receptor. KW-3902 at 10 microM showed no effect on recombinant rat A3 receptors expressed on CHO cells. 3. Saturation studies with [3H]-KW-3902 revealed that it bound with high affinity (Kd = 77 pM) and limited capacity (Bmax = 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 A1 antagonism against the inhibition of forskolin-induced cyclic AMP accumulation in DDT1 MF-2 cells by the A1-selective agonist, cyclopentyladenosine with a dissociation constant (KB value) of 0.34 nM. KW-3902 antagonized 5'-N-ethylcarboxamidoadenosine-elicited cyclic AMP accumulation via A2B receptors with a KB value of 52 nM. 5. KW-3902 exhibited marked species-dependent differences in the binding affinities. The highest affinity was for the rat A1 receptor (ki = 0.19 nM) and these values for guinea-pig and dog A1 receptors were 1.3 and 10 nM, respectively.
authors.affiliation: Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nonaka
authors.forename: M
authors.initials: M
authors.lastname: Ichimura
authors.forename: M
authors.initials: M
authors.lastname: Takeda
authors.forename: T
authors.initials: T
authors.lastname: Kanda
authors.forename: J
authors.initials: J
authors.lastname: Shimada
authors.forename: F
authors.initials: F
authors.lastname: Suzuki
authors.forename: H
authors.initials: H
authors.lastname: Kase
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism*; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis; D004232:Diuretics / Q000378:metabolism / Q000494:pharmacology*; D004285:Dogs; D006168:Guinea Pigs; D008024:Ligands; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D014970:Xanthines / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004232:Diuretics; D008024:Ligands; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014970:Xanthines; C073525:rolofylline; D000242:Cyclic AMP; D000241:Adenosine