PURINERGIC DRUGS - OPPORTUNITIES IN THE 1990S

The premise that purinergic nucleosides and nucleotides subserve roles as autocrine agents, neurotransmitters, or neuromodulators has been well established over the past 20 years. Mechanistically, adenosine, the endogenous ligand for P1 type purinoceptors, acts to modulate the release of a variety of neurotransmitters as well as modulating the effects of such agents at the postsynaptic level. P2 receptor agonists, including ATP and ADP, appear to act more like traditional neurotransmitters undergoing quantal release and producing their effects directly through G-protein linked receptors or ligand gated ion channels. There is, however, little direct evidence at this time for pathophysiologies directly attributable to purinoceptor malfunction. Nonetheless, the adenosine formed from ATP breakdown appears to play a protective role in hypoxic and ischemic situations. And adenosine A1 agonists as well as agents that act to potentiate the actions of endogenous adenosine (AlCA riboside, adenosine uptake blockers, adenosine kinase inhibitors etc.) are being evaluated for use in stroke and reperfusion injury. A1 receptor agonists may also have potential as anticonvulsants and in the treatment of type II diabetes. A2a receptor ligands because of their unique co-localization with D2 receptor containing neurons in the striatopalladial pathway of the basal ganglia may have potential use in the treatment of diseases involving dopaminergic malfunction for instance, Parkinsonism and schizophrenia. Agonist therapy may, however, be limited by the non-specific actions of agonists at nontarget tissues and the tolerance typically associated with chronic agonist therapy. As a result, there is increased focus on indirect modulation of adenosine systems by either adenosine potentiators or allosteric modulators, the latter class including PD 81, 723 and the newly discovered peptide, adenoregulin. Approaches to adenosine antagonists as therapeutic agents have resulted in the identification of 8-substituted xanthines including KFM 19 and MDL 102, 234 that are currently being evaluated as cognition enhancers with potential use in Alzheimer's disease. While chemistry in the area of P2 purinoceptor has been limited, ATP itself may have potential use in the treatment of cancer and shock. Continued progress in the understanding of the physiological role of the various classes of purinoceptor has the potential to lead to novel therapeutics in the 1990s.