Dog Coronary Artery Adenosine Receptor: Structure of N6-Aryl Subregion

Article abstract of DOI:10.1021/jm00156a016

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 and aryl subregionthat 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.