Dog coronary artery adenosine receptor: structure of the N6-alkyl subregion.
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 R diastereomer 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 of 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.
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D007536:Isomerism; D008968:Molecular Conformation; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011983:Receptors, Purinergic; D013329:Structure-Activity Relationship
D011956:Receptors, Cell Surface; D011983:Receptors, Purinergic; C047235:N-(1-methyl-2-phenylethyl)adenosine; D000241:Adenosine