Selectivity of action of 8-alkylamino analogues of N6-cyclopentyladenosine in vivo: haemodynamic versus anti-lipolytic responses in rats.

1. A1 adenosine receptor agonists with reduced intrinsic activity may be therapeutically useful as result of an increased selectivity of action. In this study the tissue selectivity of three 8-alkylamino substituted analogues of N6-cyclopentyladenosine (CPA) was investigated for haemodynamic and anti-lipolytic effects using an integrated pharmacokinetic-pharmacodynamic approach.

5'-substituted adenosine analogs as new high-affinity partial agonists for the adenosine A1 receptor.

5'-(Alkylthio)-, 5'-(methylseleno)-, and 5'-(alkylamino)-substituted analogues of N6-cyclopen-tyladenosine (CPA) were synthesized in 30-50% overall yields. The affinities of these compounds for the adenosine A1 and A2A receptors were determined in rat brain membranes. The 5'-substituted CPA analogues proved selective for the adenosine A1 receptors, displaying affinities in the nanomolar range.

8-Alkylamino-substituted analogs of N6-cyclopentyladenosine are partial agonists for the cardiovascular adenosine A1 receptors in vivo.

Partial adenosine A1 receptor agonists with reduced intrinsic activity at the cardiovascular system would be promising for therapeutic application (e.g., as antilipolytic agents).

N6,C8-distributed adenosine derivatives as partial agonists for adenosine A1 receptors.

The synthesis and biological evaluation of N6, C8-disubstituted derivatives of adenosine as potential partial agonists for adenosine receptors is described. Via three routes, two series of compounds were prepared, viz., N6-cyclopentyladenosine derivatives 3a-e and C8-(cyclopentylamino)adenosine analogs 3e and 9a-d, respectively.

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.