P2-receptor agonists: From molecular recognition studies to potential clinical applications

The elucidation of the parameters governing molecular recognition of modified-adenine nucleotides by P2Y-receptors is described. In addition, parameters effecting the enzymatic stability of these and other P2-R ligands, towards NTPDase, a major enzyme in extracellular nucleotides metabolism, are also discussed. These findings are significant for the development of potent and enzymatically stable P2Y-R ligands. Furthermore, 8-thioether-ATP derivatives, found inactive at P2Y- and P2X-receptors, and stable to NTPDase hydrolysis, were developed as specific and potent NTPDase inhibitors. The latter are important for potentiation of the pharmacological effect of endogenous ATP and ADP and of synthetic P2-R ligands. The knowledge described above was used to develop two new series of pharmacologically active P2-R ligands. Thus, a series of 2-thioether-ATP-α-S derivatives was synthesized. These compounds were identified as potent P2Y₁-R ligands and potent insulin secretagogues, active at nM concentrations. These analogues also possess relative enzymatic stability and high chemical stability. However, their ability to also induce vascular effects prevents their further use as potential anti-diabetic agents. In addition, a series of non-nucleotide P2X-Rs ligands with cardiac activity was identified. These ligands are xanthine-alkylphosphates, which exert the same effects as ATP regarding Ca²⁺ elevation and contractility of cardiac cells. Owing to the selectivity of these ligands to certain P2X-R subtypes, they are expected to serve as prototypes for selective compounds aiming at cardiac disorders mediated through certain P2X-receptors. (C) 2000 Wiley-Liss, Inc.