A NOVEL NONXANTHINE ADENOSINE A(1) RECEPTOR ANTAGONIST

FK453, )-[(E)-3-(2-phenylpyrazolo[1,5-alpha]pyridin-3-yl) acryloyl]-2- piperidine ethanol, was examined for adenosine receptor antagonistic a ctivity using isolated guinea-pig atria and aorta and for affinity for adenosine receptors in the rat cerebral cortex and striatum in compar ison with FR113452 (S enantiomer of FK453), PD116948 (1,3-dipropyl-8-c yclopentylxanthine), 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 mu M adenosine with an IC50 of 560 pM in guinea-pig atria. However, FK453 was less potent in inhibiting the relaxation induced by 3.2 mu M adenosine and had an IC 50 of 1.18 mu M in guinea-pig aorta. The IC50 values for FR113452, PD1 16948, theophylline and CGS15943 were 1.18 mu M, 1.31 nM, 20.2 mu M an d 74.2 nM in atria and > 100 mu M, 656 nM, 239 mu M, 127 nM in aorta r espectively. In the binding study, FK453 antagonized [H-3]N-6-cyclohex yladenosine binding to the rat cortical adenosine A(1) receptor with a n IC50 of 17.2 nM. The IC50 values for FR113452, PD116948, theophyllin e and CGS15943 were 10.1 mu M, 4.7 nM, 67.7 mu M and 241 nM respective ly. FK453 inhibited [H-3]5'-N-ethylcarboxamideadenosine binding to rat striatum adenosine A(2) receptor with an IC50 of 11.3 mu M. FK453 had no adenosine A(1) receptor agonistic activity, since it had no negati ve inotropic activity up to 100 mu M in isolated guinea-pig atria. The se results demonstrate that FK453 is a novel non-xanthine adenosine re ceptor antagonist and is potent and selective for the adenosine A(1) r eceptor subtype.