P2 purine and pyrimidine receptors: Emerging superfamilies of G-protein-coupled and ligand-gated ion channel receptors

Against a background of considerable skepticism and limited efforts in medicinal chemistry, the pivotal role of adenosine triphosphate (ATP) and related nucleotides as neurotransmitters and/or neuromodulators has been firmly established in the past decade. At least 15 receptor subtypes have been cloned, seven from the ligand gated ion channel (LGIC) P2X superfamily and eight from the G-protein-coupled receptor (GPCR) P2Y superfamily. All agonist pharmacophores for the P2 receptor superfamily with the exception of some recently described theobromine analogs are modified forms of the natural ligands ATP, adenosine diphosphate (ADP) or uridine triphosphate (UTP). On the other hand, antagonist ligands represent a diverse group of compounds. These include: the 2'- and 3'-phosphate analogs of ATP, eg, A3P5PS; the antitrypanosomal agent, suramin, the suramin analogs, XAMR0721, NF023 and BSt101; PPADS (pyridoxal phosphate-6-azaphenyl-2',4'-disulfonic acid); DIDS (4,4'-diisothiocyanotostilbene-2,2'-disulfonate) and a series of isothiocyanato sulfonates related to DIDS that includes beta-INS; and a series of chromophores-that include, reactive red 2, trypan blue, Cibachrome blue, Evans blue and the desmethyl derivative of Evans blue, NH01. Such agents demonstrate varying degrees of potency and selectivity, in general limiting their usefulness in characterizing P2 receptor function especially at the in vivo level. With an increasing number of potential receptor tar ets being identified by cloning techniques, the use of modern medicinal chemistry technologies (eg, combinatorial chemistry, computer-assisted molecular design) together with the high throughput screening of compound libraries and natural product sources offers a considerable opportunity to advance the therapeutic potential for P2 purinoceptor targeted molecules in the immediate future. In addition, the identification of allosteric modulators of P2 receptor function like PIT (2,2'-pyridylisatogen tosylate) and d-tubocurarine potentially provides a more subtle approach to modulation of receptor function that is comparable to the effects (and therapeutic promise) of benzodiazepines in modulating GABA-A receptor function.