8-substituted adenosine and theophylline-7-riboside analogues as potential partial agonists for the adenosine A1 receptor.
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.
Van der Wenden
E M
EM
Division of Medicinal Chemistry, Leiden-Amsterdam Center for Drug Research, Leiden University, The Netherlands.
Hartog-Witte
H R
HR
Roelen
H C
HC
von Frijtag Drabbe Künzel
J K
JK
Pirovano
I M
IM
Mathôt
R A
RA
Danhof
M
M
Van Aerschot
A
A
Lidaks
M J
MJ
IJzerman
A P
AP
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
D058906:Purinergic P1 Receptor Agonists; D014970:Xanthines; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline; D000262:Adenylyl Cyclases; D000241:Adenosine