Potent agonist action of 2-thioether derivatives of adenine nucleotides at adenylyl cyclase-linked P2Y-purinoceptors.

1. Analogues of adenine nucleotides inhibited beta-adrenoceptor-stimulated cyclic AMP accumulation in C6 rat glioma cells with a pharmacological selectivity consistent with that for involvement of a P2Y-purinoceptor. 2. The inhibitory effect of adenine nucleotides was completely prevented by pretreatment of cells with pertussis toxin. 3. The capacity of a series of recently synthesized 2-thioether analogues of adenine nucleotides to inhibit cyclic AMP accumulation was examined. Several ATP analogues, e.g. 2-cyclohexylthio and 2-hexylthio ATP, inhibited cyclic AMP accumulation with EC50 values of approximately 30 pM. These values represent 100,000 fold increases in potency over ATP. 4. Analogues of ADP exhibited the same remarkable increase in potency relative to their natural congener and diphosphates were at least as potent as the corresponding triphosphates at the C6 cell P2Y-purinoceptor. 5. The relative potencies of a broad series of agonists at the C6 cell receptor did not correspond to the relative potencies of the same compounds for activation of P2Y-purinoceptors on turkey erythrocyte membranes. Some agonists, particularly 2-thioether derivatives were more potent for stimulation of the C6 cell receptor, whereas other agonists were more potent in the turkey erythrocyte system. 6. These results add further support to the view that the adenylyl cyclase-linked P2Y-purinoceptor of C6 rat glioma cells is a different subtype from the phospholipase C-linked P2Y-purinoceptor of turkey erythrocyte membranes and several mammalian tissues.