POTENT AGONIST ACTION OF 2-THIOETHER DERIVATIVES OF ADENINE-NUCLEOTIDES AT ADENYLYL CYCLASE-LINKED P-2Y-PURINOCEPTORS

1 Analogues of adenine nucleotides inhibited beta-adrenoceptor-stimula ted cyclic AMP accumulation in C6 rat glioma cells with a pharmacologi cal selectivity consistent with that for involvement of a P-2Y-purinoc eptor. 2 The inhibitory effect of adenine nucleotides was completely p revented 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 A TP analogues, e.g. 2-cyclohexylthio and 2-hexylthio ATP, inhibited cyc lic AMP accumulation with EC(50) values of approximately 30 pM. These values represent 100,000 fold increases in potency over ATP. 4 Analogu es of ADP exhibited the same remarkable increase in potency relative t o their natural congener and diphosphates were at least as potent as t he corresponding triphosphates at the C6 cell P-2Y-purinoceptor. 5 The relative potencies of a broad series of agonists at the C6 cell recep tor did not correspond to the relative potencies of the same compounds for activation of P-2Y-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 m ore potent in the turkey erythrocyte system. 6 These results add furth er support to the view that the adenylyl cyclase-linked P-2Y-purinocep tor of C6 rat glioma cells is a different subtype from the phospholipa se C-linked P-2Y-purinoceptor of turkey erythrocyte membranes and seve ral mammalian tissues