N-cycloalkyl derivatives of adenosine and 1-deazaadenosine as agonists andpartial agonists of the A(1) adenosine receptor

A number of cycloalkyl substituents (from C-3 to C-8) have been int-reduced on the 6-amino group of adenosine, 1-deazaadenosine, and 2'-deoxyadenosine , bearing or not a chlorine atom at the 2-position, to evaluate the influen ce on the A(1) and A(2A) affinity of steric hindrance and lipophilicity. Fu rthermore, the guanosine 5'-triphosphate (GTP) shift and the maximal induct ion of guanosine 5'-(gamma-thio)triphosphate ([S-35]GTP gamma S) binding to G proteins in rat brain membranes were used to determine the intrinsic act ivity of these nucleosides at the A(1) adenosine receptor. All compounds of the ribose-bearing series proved to be full agonists, the 1-deaza derivati ves showing affinities for the Al receptor about 10-fold lower than the cor responding adenosines. On the other hand, all the 2'-deoxyribose derivative s bind to the A(1) receptor with affinities in the high nanomolar range, wi th the 2-chloro substituted compounds showing slightly higher affinities th an the 2-unsubstituted counterparts. In terms of the potencies, the most po tent compounds proved to be those bearing four- and five-membered rings. Bo th GTP shifts and [S-35]-GTP gamma S experiments showed that most of the 2' -deoxyadenosine derivatives are partial agonists, The 2'-deoxyadenosine der ivatives which were identified as partial agonists consistently detected fe wer Az receptors in the high-affinity state than full agonists. However, it is worthwhile noting that there was not a simple Linear relationship betwe en receptor occupancy and activation. These results indicate that a critica l density of A(1) adenosine receptors in the high-affinity state is require d for G protein activation.