Agonists and antagonists acting at P2X receptors: selectivity profiles andfunctional implications

P2X receptors are nucleotide-gated cation channels composed of homomeric or heteromeric assemblies of three subunits. In the past 7 years, an extended series (P2X(1-7)) of P2X subunits has been cloned from vertebrate tissues. In this rapidly expanding field, one of the main current challenges is to relate the cloned P2X receptor subtypes to the diverse physiological respon ses mediated by the native P2X receptors. However, the paucity of useful li gands, especially subtype-selective agonists and antagonists as well as rad ioligands, acts as a considerable impediment to progress. Most of the ligan ds available are highly limited in terms of their kinetics of action, recep tor-affinity, subtype-selectivity and P2X receptor-specificity. Their suspe cted ability to be a substrate for ecto-nucleotidases or to inhibit these e nzymes also complicates their use. A number of new antagonists at P2X recep tors have recently been described which to some degree are more potent and more selective than earlier antagonists like suramin or pyridoxal-5'-phosph ate-6-azophenyl 2',4'-disulfonate (PPADS). This work moves us closer to the ideal goal of classifying the recombinant and native P2X receptor subtypes on the basis of antagonist profiles. This review begins with a brief accou nt of the current status of P2X receptors. It then focuses on the pharmacol ogical properties of a series of key P2 receptor agonists and antagonists a nd will finish with the discussion of some related therapeutic possibilitie s.