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

The elucidation of the parameters governing molecular recognition of modifi ed-adenine nucleotides by P2Y-receptors is described. In addition, paramete rs effecting the enzymatic stability of these and other P2-R ligands, towar ds NTPDase, a major enzyme in extracellular nucleotides metabolism, are als o discussed. These findings are significant for the development of potent a nd enzymatically stable P2Y-R ligands. Furthermore, 8-thioether-ATP derivat ives, found inactive at P2Y- and P2X-receptors, and stable to NTPDase hydro lysis, 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 w as used to develop two new series of pharmacologically active P2-R ligands. Thus, a series of 2-thioether-ATP-alpha-S derivatives was synthesized. The se compounds were identified as potent P2Y(1)-R ligands and potent insulin secretagogues, active at nM concentrations. These analogues also possess re lative enzymatic stability and high chemical stability. However, their abil ity to also induce vascular effects prevents their further use as potential anti-diabetic agents. In addition, a series of non-nucleotide P2X-Rs ligan ds with cardiac activity was identified. These ligands are xanthine-alkylph osphates, which exert the same effects as ATP regarding Ca2+ elevation and contractility of cardiac cells. Owing to the selectivity of these ligands t o certain P2X-R subtypes, they are expected to serve as prototypes for sele ctive compounds aiming at cardiac disorders mediated through certain P2X-re ceptors. Drug Dev. Res. 50:338-354, 2000. (C) 2000 Wiley-Liss, Inc.