Adenosine regulates a wide range of physiological functions through interaction with at least two major classes of adenosine receptors. The A1 and A3 classes of adenosine receptors are inhibitory to adenylate cyclase, while the A2 class is stimulatory to adenylate cyclase. Subclasses of adenosine receptors also occur. Some of these are inhibitory to calcium channels, some are stimulatory to potassium channels, some activate guanylate cyclase, some modulate phospholipid turn-over and some cause smooth muscle relaxation. A series of pyrazolopyridines were synthesized. The ethyl 1-ethyl-4- butylaminopyrazolopyridine-5-carboxylate was a non-specific A1- and A2a- adenosine receptor antagonist with a potency some 50-fold greater than theophylline. Adenoregulin, a peptide isolated from an Amazonian hylid frog and mastoparan, a wasp peptide, both markedly stimulate binding of agonists to A1, alpha-2 and 5-HT1A receptors. All of these receptors are coupled via Gi-class proteins to adenylate cyclase. Both adenoregulin and mastoparan enhance turnover of guanylnucleotides at Gi proteins. It appears that enhancement of binding of agonists to receptors by these peptides is due to conversion of the receptor-G-protein complex to a high-affinity guanyl nucleotide-free state. No evidence for direct functional activation of phospholipase C by adenoregulin or mastoparan was obtained. Instead, the peptides were inhibitory to phosphoinositide breakdown in permeabilized cells. Chronic caffeine ingestion by mice causes increases in density of A1-adenosine, serotonin, cholinergic and GABAA-receptors and L-type calcium channels and decreases in beta- adrenergic receptors. A2a-Adenosine, alpha-adrenergic, dopaminergic and NMDA receptors appear unaltered. Behavioral responses to adenosine analogs, caffeine, cholinergic and dopaminergic agents are altered after chronic caffeine. The behavioral depressant effects of ethanol are markedly decreased after chronic caffeine.
