Dog coronary artery adenosine receptor: structure of the N6-aryl subregion

Previous structure-coronary vasoactivity correlations of the N6-alkyladenosine analogues of N6-[(R)-1-phenyl-2-propyl]adenosine, 1, support the hypothesis that the coronary artery A2 adenosine receptor contains an N6 region of specialized structure. The part of this receptor region that binds the 2-propyl moiety of 1 determines stereoselectivity and contributes to coronary vasoactivity. The present study uses 92 adenosine analogues containing an aryl group in the N6 substituent to test the hypothesis that the N6 receptor region contains an aryl subregion that binds the phenyl moiety of 1 and thereby contributes to its coronary vasoactivity. N6-Aralkyladenosines are often more potent than their alkyl congeners. Two methylene residues seem to provide optimum separation of the aryl group from N6. Among adenosines with semirigid N6 substituents, N6-[(1R,2S)-trans-2-phenylcyclohexyl]adenosine was uniquely active, evidence that when 1 occupies the receptor, the axis of the propyl C-1 to phenyl C-1 bond is nearly in the plane described by N6 and propyl C-1 and C-2. The torsion angle around this bond is unknown. Replacing the phenyl group of N6-2-phenethyladenosine with a thienyl or a 3-pyridyl group raises activity. The structure-activity relationships of the N6-(arylethyl)-, the N6-(arylmethyl)-, and the N6-phenyladenosines differ strinkingly from each other. Taken together, such results support the idea that the N6 region of the dog coronary artery A2 adenosine receptor includes an aryl subregion.