title: 8-substituted adenosine and theophylline-7-riboside analogues as potential partial agonists for the adenosine A1 receptor.
abstract: A series of 8-substituted adenosine and theophylline-7-riboside analogues (28 and 9 compounds, respectively) was tested on adenosine A1 and A2A receptors as an extensive exploration of the adenosine C8-region. Alkylamino substituents at the 8-position cause an affinity decrease for adenosine analogues, but an affinity increase for theophylline-7-riboside derivatives. The affinity decrease is probably due to a direct steric hindrance between the C8-substituent and the binding site as well as to electronic effects, not to a steric influence on the ribose moiety to adopt the anti conformation. The 8-substituents increase the affinity of theophylline-7-riboside analogues probably by binding to a lipophilic binding site. The intrinsic activity was tested in vitro for some 8-substituted adenosine analogues, by determining the GTP shift in receptor binding studies and the inhibition of adenylate cyclase in a culture of rat thyroid FRTL-5 cells, and in vivo in the rat cardiovascular system for 8-butylaminoadenosine. Thus, it was shown that 8-ethyl-, 8-butyl-, and 8-pentylamino substituted analogues of adenosine may be partial agonists in vitro, and that 8-butylaminoadenosine is a partial agonist for the rat cardiovascular A1 receptor in vivo.
authors.affiliation: Division of Medicinal Chemistry, Leiden-Amsterdam Center for Drug Research, Leiden University, The Netherlands.
authors.forename: E M
authors.initials: EM
authors.lastname: Van der Wenden
authors.forename: H R
authors.initials: HR
authors.lastname: Hartog-Witte
authors.forename: H C
authors.initials: HC
authors.lastname: Roelen
authors.forename: J K
authors.initials: JK
authors.lastname: von Frijtag Drabbe Künzel
authors.forename: I M
authors.initials: IM
authors.lastname: Pirovano
authors.forename: R A
authors.initials: RA
authors.lastname: Mathôt
authors.forename: M
authors.initials: M
authors.lastname: Danhof
authors.forename: A
authors.initials: A
authors.lastname: Van Aerschot
authors.forename: M J
authors.initials: MJ
authors.lastname: Lidaks
authors.forename: A P
authors.initials: AP
authors.lastname: IJzerman
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D013806:Theophylline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D014970:Xanthines / Q000494:pharmacology
chemical_list: D058906:Purinergic P1 Receptor Agonists; D014970:Xanthines; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline; D000262:Adenylyl Cyclases; D000241:Adenosine