8-SUBSTITUTED ADENOSINE AND THEOPHYLLINE-7-RIBOSIDE ANALOGS AS POTENTIAL PARTIAL AGONISTS FOR THE ADENOSINE A(1) RECEPTOR

A series of 8-substituted adenosine and theophylline-7-riboside analog ues (28 and 9 compounds, respectively) was tested on adenosine A(1) an d A(2A) receptors as an extensive exploration of the adenosine C8-regi on. Alkylamino substituents at the 8-position cause an affinity decrea se for adenosine analogues, but an affinity increase for theophyliine- 7-riboside derivatives. The affinity decrease is probably due to a dir ect steric hindrance between the C8-substituent and the binding site a s well as to electronic effects, not to a steric influence on the ribo se 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 vit ro for some 8-substituted adenosine analogues, by determining the GTP shift in receptor binding studies and the inhibition of adenylate cycl ase in a culture of rat thyroid FRTL-5 cells, and in vivo in the rat c ardiovascular system for 8-butylaminoadenosine. Thus, it was shown tha t 8-ethyl-, 8-butyl-, and 8-pentylamino substituted analogues of adeno sine may be partial agonists in vitro, and that 8-butylaminoadenosine is a partial agonist for the rat cardiovascular Al receptor in vivo.