The accumulations of cyclic AMP elicited by agonists for A2-adenosine, beta-adrenergic, H2-histamine and VIP receptors in brain tissue are markedly augmented by agonists that enhance the turnover of phosphatidylinositol through interaction with alphal-adrenergic, H1-histamine and 5HT-serotonin receptors. The potentiation of receptor and forskolin-mediated responses of cyclic AMP-generating systems appears likely due primarily to formation of diacylglycerols and activation of protein kinase C, rather than to the concomitant formation of inositol phosphates and release of internal calcium: Phorbol esters that directly effect protein kinase C also augment responses of cyclic AMP-generating systems, but do not further augment responses due to combinations of 2-chloro-adenosine with agents that cause phosphatidylinositol turnover. Adenosine receptors, apparently of the A1-subclass, appear involved in a selective augmentation of histamine-elicited accumulations of inositolphosphates in brain tissue. The high affinity binding of forskolin to membranes appears associated with a complex of adenylate cyclase and activated stimulatory guanine nucleotide protein and is enhanced by cations, fluoride and guanylnucleotides. The response of cyclic AMP-generating systems in platelets to combinations of forskolin and prostaglandins is refractory to inhibition by alpha2-adrenergic agonists or a P-site agent, 2',5'-dideoxyadenosine. Forskolin markedly potentiates leukotriene-elicited plasma exudation in rat skin. Some of a wide range of N6-substituted adenosines exhibit selectivity or even specificity for a brain A1-adenosine receptor compared to a coronary A2-receptor. These adenosine analogs have allowed a detailed analysis of the topography of the N6-subregion of adenosine receptors. Potent water soluble adenosine antagonists have been developed. These include 1,3-dipropyl-8-(p-sulfophenyl)xanthine. Other 8-phenylxanthine derivatives exhibit marked selectivity as antagonists for A1-receptors. Certain caffeine analogs, such as 1,3-dipropyl-7-methylxanthine, exhibit some selectivity as antagonists for A2-receptors.
