Dog Coronary Artery Adenosine Receptor: Structure of the N6-Alkyl Subregion

Article abstract of DOI:10.1021/jm00149a016

The moderately potent and stereoselective coronary vasoactivity of N⁶-<1-phenyl-2(R)-propyl>adenosine (1) is the basis for the present study that maps the N⁶ region of the coronary artery adenosine receptor by means of the structure-coronary vasoactivity relationships of 81 analogues of 1 in the open-thorax dog.Stereoselectivity is a general property of N⁶-substituted adenosines that have a chiral center adjacent to N⁶.The activity ratio of 1 to its S diastereomer is 10, the result of the positive interaction with the receptor of the propyl C-3 group of the Rdiastereomer in combination with the steric hindrance exerted by this group of the S diastereomer.Replacing the benzyl moiety of 1 by an ethyl, phenyl, phenethyl, or naphthyl group lowers potency of the R diastereomer and, accordingly, the R/S ratio.Propyl C-1 interacts with a receptor region large enough to accommodate three methylene residues and the propyl C-3 residue with a separate region large enough to accommodate two.The receptor subregion that interacts with the propyl C-1 of 1 is more tolerant of bulk and of polar substituents than the subregion that interacts with propyl C-3.Evidence bearing on the possible contribution of N⁶ to activity, e.g. through hydrogen bonding, is ambiguous.These results support a provisional model of the N⁶-alkyl subregion.