1,3-DIPROPYL-8-[2-(5,6-EPOXY)NORBORNYL]XANTHINE, A POTENT, SPECIFIC AND SELECTIVE A(1) ADENOSINE RECEPTOR ANTAGONIST IN THE GUINEA-PIG HEART AND BRAIN AND IN DDT(1)MF-2 CELLS

The objective of this study was to characterize the adenosine receptor (AdoR) antagonistic properties of a newly synthesized alkylxanthine, 1,3-dipropyl-8[2-(5,6-epoxy)norbornyl]xanthine (ENX), and compare them to those of 1,3-dipropyl-8-(cyclopentyl)xanthine (CPX), 1,3-dipropyl- 8-(3-noradamantyl)xanthine (NAX) and (+/-)-N-G-endo-norbornan-2-yl-9-m ethyladenine (N-0861). The potencies and selectivities of ENX, CPX, NA X and N-0861 were determined by functional studies of guinea pig isola ted perfused hearts, and by radioligand binding assays for A(1) and A( 2a) AdoRs in the guinea pig forebrain and striatum. ENX competitively antagonized A(1) AdoR-mediated prolongations of atrioventricular nodal conduction time caused by Ado or by 2-chloro-N-G-cyclopentyladenosine , but not those caused by carbachol (0.14 mu M) or MgCl2 (3 mM). Schil d analysis of 2-chloro-N-G-cyclopentyladenosine-antagonist competition curves yielded pA(2) values for ENX, CPX and NAX of 8.45 +/- 0.19, 8. 55 +/- 0.28 and 8.79 +/- 0.15, respectively. ENX (30 mu M) and N-0861 (30 mu M) did not attenuate the A, AdoR-mediated increase in coronary conductance caused by adenosine. CPX and NAX attenuated the coronary v asodilation caused by adenosine with IC50 values of 1.5 and 7.1 mu M, respectively. Radioligand binding assays revealed that ENX, CPX and NA X and N-0861 had a 400-, 209-, 110- and 10-fold greater affinity, resp ectively, for A(1) than for A(2a) AdoRs of guinea pig brain membranes. Thus, ENX was equipotent with CPX and NAX and more potent than N-0861 (pA(2) = 6.2) as an antagonist at A, AdoRs, but had lower affinity fo r A(1) AdoRs in guinea pig hearts and brain striatum than did either C PX or NAX. In DDT1 MF-2 cells, all three alkylxanthines had similar af finities for A(1) AdoRs, whereas the affinity of N-0861 for A, AdoRs w as significantly lower. ENX appears to be the most A(1) AdoR subtype-s elective of the alkylxanthine class of AdoR antagonists reported to da te.