Structure-activity relationship of 2-(ar) alkoxyadenosines at the adenosine A2 receptor in coronary artery

We examined the ability of four 2-(ar)alkoxyadenosines (2-(2-phenylethoxy)adenosine, PEA; 2-[2-(2-naphthyl)ethoxy]adenosine, NEA; 2-[2-(4-methylphenyl)ethoxy]adenosine, mPEA; 2-(1-hexyloxy)adenosine, HOA) to relax porcine coronary artery in vitro. All four compounds produced concentration-dependent relaxations in rings contracted with 30 mM KCl. The EC25 values are as follows (x 10(-9) mol/l): CGS21680, (2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosi ne) (32.7) approximately NECA, 5'-N-ethylcarboxamidoadenosine (51.4) approximately mPEA (74.3) approximately NEA (160.7) > HOA (855.1) approximately PEA (1259) approximately 2-chloroadenosine (1871) > adenosine (9705). However, EC75 values for all the compounds except adenosine and 2-chloroadenosine converged to a range of 8.16 to 22.86 microM, suggesting a biphasic response. Furthermore, the responses were found to be independent of endothelial integrity. The unselective adenosine receptor antagonist 8-p-sulphophenyltheophylline (100 microM) attenuated the relaxant response to NEA (EC25 = 1172 nM), suggesting that adenosine receptors mediated relaxation. Structure-activity correlations suggest that the adenosine A2 receptor in porcine coronary artery contains a region of limited bulk tolerance juxtaposed to the region occupied by adenine C-2 and distal to that a large hydrophobic region.