Novel short-acting A(2A) adenosine receptor agonists for coronary vasodilation: Inverse relationship between affinity and duration of action of A(2A)agonists

Several potent and selective A(2A) adenosine receptor agonists are currentl y available. These compounds have a high affinity for the A(2A) receptor an d a long duration of action. However, in situations where a short duration of action is desired, currently available A(2A) receptor agonists are less than ideal. From a series of recently synthesized A(2A) receptor agonists, two agonists (CVT-3146 and CVT-3033) with low affinity were selected for fu rther characterization as selective and short-acting coronary vasodilators. Both compounds were selective for the A(2A) adenosine receptor (AdoR) vers us the A(1), A(2B), and A(3)AdoR in binding and functional studies. CVT-314 6 and CVT-3033 appeared to be weak partial agonists to cause cAMP accumulat ion in PC12 cells, but were full and potent agonists to cause coronary vaso dilation, a response that has a very large A(2A) receptor reserve. However, the durations of action of CVT-3146 and CVT-3033 were remarkably shorter t han those of the high-affinity agonists CGS21680 or WRC0470, presumably due to the relative lower affinity of CVT-3146 and CVT-3033 for the A(2A) rece ptor. Indeed, an inverse relationship was found between the affinity of the various agonists for the A(2A) receptor and the duration of their actions. These data indicate that low-affinity agonists can produce a response that is of equivalent magnitude but more rapid in termination than that caused by a high-affinity agonist. Hence, the low-affinity A(2A) agonists CVT-3146 and CVT-3033 may prove to be superior to currently available high-affinity agonists as coronary vasodilators during myocardial imaging with radionucl ide agents.