A novel non-xanthine adenosine A1 receptor antagonist

FK453, (+)-(R)-[(E)-3-(2-phenylpyrazolo[1,5-alpha]pyridin-3-yl) acryloyl]-2-piperidine ethanol, was examined for adenosine receptor antagonistic activity using isolated guinea-pig atria and aorta and for affinity for adenosine receptors in the rat cerebral cortex and striatum in comparison with FR113452 (S enantiomer of FK453), PD116948 (1,3-dipropyl-8-cyclopentylxanthine), theophylline (1,3-dimethylxanthine) and CGS15943 ([1,2,4]triazolo[1,5-c]quinazolone). FK453 showed potent inhibition of the negative inotropic activity elicited by 10 microM adenosine with an IC50 of 560 pM in guinea-pig atria. However, FK453 was less potent in inhibiting the relaxation induced by 3.2 microM adenosine and had an IC50 of 1.18 microM in guinea-pig aorta. The IC50 values for FR113452, PD116948, theophylline and CGS15943 were 1.18 microM, 1.31 nM, 20.2 microM and 74.2 nM in atria and > 100 microM, 656 nM, 239 microM, 127 nM in aorta respectively. In the binding study, FK453 antagonized [3H]N6-cyclohexyladenosine binding to the rat cortical adenosine A1 receptor with an IC50 of 17.2 nM. The IC50 values for FR113452, PD116948, theophylline and CGS15943 were 10.1 microM, 4.7 nM, 67.7 microM and 241 nM respectively. FK453 inhibited [3H]5'-N-ethylcarboxamideadenosine binding to rat striatum adenosine A2 receptor with an IC50 of 11.3 microM. FK453 had no adenosine A1 receptor agonistic activity, since it had no negative inotropic activity up to 100 microM in isolated guinea-pig atria. These results demonstrate that FK453 is a novel non-xanthine adenosine receptor antagonist and is potent and selective for the adenosine A1 receptor subtype.