title: Ribose-modified adenosine analogues as potential partial agonists for the adenosine receptor.
abstract: We have adopted a practical three-step route for the synthesis of 2'- and 3'-deoxy analogues of N6-substituted adenosines: protection of the hydroxyl groups, replacement of the N6-amino by a better leaving group, and combined deprotection and N6-amination in the last step. This route was used to synthesize deoxy analogues of CPA, CHA, and R- and S-PIA. The compounds were tested on the adenosine A1 and A2a receptors in our search for partial agonists for these receptors. The GTP shift was used as an in vitro measure for the intrinsic activity of these compounds; the in vivo intrinsic activities of the deoxy analogues of CPA and R-PIA were determined in the rat cardiovascular system. Thus, it was shown that the hydroxyl groups are determinants for the affinity and intrinsic activity of these analogues. Removal of the 2'- and 3'-hydroxyl groups affects affinity and intrinsic activity, whereas removal of the 5'-hydroxyl group decreases only affinity.
authors.affiliation: Leiden-Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, The Netherlands.
authors.forename: E M
authors.initials: EM
authors.lastname: van der Wenden
authors.forename: J K
authors.initials: JK
authors.lastname: von Frijtag Drabbe Künzel
authors.forename: R A
authors.initials: RA
authors.lastname: Mathôt
authors.forename: M
authors.initials: M
authors.lastname: Danhof
authors.forename: A P
authors.initials: AP
authors.lastname: IJzerman
authors.forename: W
authors.initials: W
authors.lastname: Soudijn
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D017208:Rats, Wistar; D012266:Ribose; D013329:Structure-Activity Relationship
chemical_list: D058906:Purinergic P1 Receptor Agonists; D012266:Ribose; D006160:Guanosine Triphosphate; D000241:Adenosine