STRUCTURE-ACTIVITY RELATIONSHIP OF 2-(AR)ALKOXYADENOSINES AT THE ADENOSINE-A(2) RECEPTOR IN CORONARY-ARTERY

We examined the ability of four 2-(ar)alkoxyadenosines (2-(2-phenyleth oxy)adenosine, PEA; 2-[2-(2-naphthyl)ethoxy]adenosine, NEA; 2-[2-(4-me thylphenyl)ethoxy]adenosine, mPEA; 2-(1-hexyloxy)adenosine, HOA) to re lax porcine coronary artery in vitro. All four compounds produced conc entration-dependent relaxations in rings contracted with 30 mM KCl. Th e EC25 values are as follows (x 10(-9) mol/l): CGS21680, yl)phenethyla mino]-5'-N-ethylcarboxamidoadenosine) (32.7) almost-equal-to NECA, 5'- N-ethylcarboxamidoadenosine (51.4) almost-equal-to mPEA (74.3) almost- equal-to NEA (160.7) > HOA (855.1) almost-equal-to PEA (1259) almost-e qual-to 2-chloroadenosine (1871) > adenosine (9705). However, EC75 val ues for all the compounds except adenosine and 2-chloroadenosine conve rged to a range of 8.16 to 22.86 muM, suggesting a biphasic response. Furthermore, the responses were found to be independent of endothelial integrity. The unselective adenosine receptor antagonist 8-p-sulphoph enyltheophylline (100 muM) attenuated the relaxant response to NEA (EC 25 = 1172 nM), suggesting that adenosine receptors mediated relaxation . Structure-activity correlations suggest that the adenosine A2 recept or in porcine coronary artery contains a region of limited bulk tolera nce juxtaposed to the region occupied by adenine C-2 and distal to tha t a large hydrophobic region.