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. Further pyrazolopyridine were synthesized and analyzed for antagonist activity at A1 and A2 adenosine receptors and for effects on diazepam-binding to GABAA receptors. Most were nonselective or were A1 receptor selective antagonists. Certain pyrazolopyridines were very potent in stimulating diazepam-binding and might therefore have anxiolytic activity. Others showed only inhibitory activity towards diazepam-binding. Adenoregulin, an amphophilic peptide from a hylid frog stimulated binding of agonists to Gi-protein-coupled receptors apparently due to conversion of the receptor-G-protein complex to a high affinity guanylnucleotide free state. Congeneric peptides from the hylid frog inhibited binding of agonists and are under investigation. Chronic caffeine or theophylline ingestion altered levels of a variety of central receptors. Only beta-adrenergic and nicotinic receptors appeared to be downregulated, suggestive of xanthine-induced increases in norepinephrine and acetylcholine turnover. Chronic theobromine, a very weak adenosine receptor antagonist, and chronic isobutylmethylxanthine, a potent adenosine receptor antagonist and, in addition, a potent phosphodiesterase inhibitor, caused, like caffeine/theophylline, upregulation of A1- adenosine receptors, but did not alter levels to other receptors. Behavioral responses to various receptor agonists/antagonists were altered after caffeine, consonant with observed changes in receptor levels.
