Adenosine: The prototypic neuromodulator.
Purinergic modulation of mammalian tissue function was first demonstrated in 1929. However, the lability of the purine and its ubiquitous distribution and function in mammalian tissues, led to a degree of scepticism as to any discrete role for the compound that resulted in a 40 year hiatus related to a concerted effort to determine the functional role of the nucleoside. Prompted by the discovery of cyclic AMP, biochemical studies in Henry McIlwain's laboratory at the Institute of Psychiatry provided some of the first evidence that adenosine might function as a chemical messenger. The subsequent discovery of cell surface recognition sites, or receptors, for adenosine that exist in two main subclasses termed A(1) and A(2) together with the availability of selective receptor antagonists generated data implicating adenosine in the pharmacological actions of several classes of centrally active agents including: anxiolytics, antipsychotics, antidepressants, cognitive enhancers and anticonvulsants. In addition, adenosine has potent effects on cardiovascular, pulmonary, renal and immune function. Effects on these systems, especially the latter, have important global implications for CNS function. These data indicate that adenosine, like the many peptides currently being studied, is a homeostatic neuromodulator and as such may represent the prototypic agent of this type. Increased efforts in the area of medicinal chemistry together with the discovery of novel structural classes that antagonize adenosine function will provide the tools for a more precise understanding of the role(s) of the purine. This may lead to new classes of therapeutic agent that act to alter modulatory, as opposed to transmitter-related, responses.
Williams
M
M
Research Department, Pharmaceuticals Division, CIBA-Geigy, Summit, NJ 07901, U.S.A.