Novel therapeutics acting via purine receptors

Abstract

A recent conference entitled Purines in Cell Signalling: Targets for New Drugs, held in Rockville, Maryland, in September, 1989, was one indication of the increasing interest in developing agonists and antagonists of P₁-(adenosine) and P₂-(ATP) purinoceptors [1] as potential therapeutic agents. Extracellular adenosine, acting at its membrane bound A₁ and A₂ receptors, is a ubiquitous modulator of cellular activity. The purine can arise from several sources including ATP hydrolysis by ectokinase activity in the region of the nerve terminal [2] and from S-adenosylhomocysteine [3] and ATP within the cell. Together with its more stable analogs, adenosine is a potent inhibitor of neurotransmitter release in both the central and peripheral nervous systems, and in cardiac, adipose and other tissues. Adenosine can also affect blood pressure and heart rate as well as modulate the function of the immune, inflammatory, gastrointestinal, renal and pulmonary systems, either via its effects on transmitter release or directly via receptor mechanisms altering intracellular transduction processes.

Fig. 1

Structures of two non-xanthine adenosine antagonists with selectivity for A₂ receptors.

Fig. 2

Enzymatic transformations of xanthine prodrugs derived from XAC, 18.

Fig. 3

Structures of R 75231 (20), an analog of the adenosine uptake inhibitor, mioflazine; the binding enhancer PD 81,723 (21); and 5-amino-4-imidazole carboxamide (AICA) riboside (22).