IDENTIFICATION OF POTENT P-2Y-PURINOCEPTOR AGONISTS THAT ARE DERIVATIVES OF ADENOSINE 5'-MONOPHOSPHATE

1 A series of chain-extended 2-thioether derivatives of adenosine mono phosphate were synthesized and tested as agonists for activation of th e phospholipase C-linked P-2Y-purinoceptor of turkey erythrocyte membr anes, the adenylyl cyclase-linked P-2Y-purinoceptor of C6 rat glioma c ells, and the cloned human P-2U-receptor stably expressed in 1321N1 hu man astrocytoma cells. 2 Although adenosine monophosphate itself was n ot an agonist in the two P-2Y-purinoceptor test systems, eleven differ ent 2-thioether-substituted adenosine monophosphate analogues were ful l agonists. The most potent of these agonists, 2-hexylthio AMP, exhibi ted an EC(50) value of 0.2 nM for activation of the C6 cell receptor. This potency was 16,000 fold greater than that of ATP and was only 10 fold less than the potency of 2-hexylthio ATP in the same system. 2-he xylthio adenosine was inactive. 3 Monophosphate analogues that were th e most potent activators of the C6 cell P-2Y-purinoceptor were also th e most potent activators of the turkey erythrocyte P-2Y-purinoceptor. However, agonists were in general more potent at the C6 cell receptor, and potency differences varied between 10 fold and 300 fold between t he two receptors. 4 Although 2-thioether derivatives of adenosine mono phosphate were potent P-2Y-purinoceptor agonists no effect of these an alogues on the human P-2U-purinoceptor were observed. 5 These results support the view that a single monophosphate is sufficient and necessa ry for full agonist activity at P-2Y-purinoceptors, and provide insigh t for strategies for development of novel P-2Y-purinoceptor agonists o f high potency and selectivity.