Negative and positive allosteric modulators of the P2X7receptor

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Abstract
Background and purpose: Antagonist effects at the P2X7receptor are complex with many behaving in a non‐competitive manner. In this study, the effects ofN‐[2‐({2‐[(2‐hydroxyethyl)amino]ethyl}amino)‐5‐quinolinyl]‐2‐tricyclo[3.3.1.13,7]dec‐1‐ylacetamide (compound‐17) andN2‐(3,4‐difluorophenyl)‐N1‐[2‐methyl‐5‐(1‐piperazinylmethyl)phenyl]glycinamide dihydrochloride (GW791343) on P2X7receptors were examined and their mechanism of action explored.Experimental approach: Antagonist effects were studied by measuring agonist‐stimulated ethidium accumulation in cells expressing human or rat recombinant P2X7receptors and in radioligand binding studies.Key results: Compound‐17 and GW791343 were non‐competitive inhibitors of human P2X7receptors. Receptor protection studies using decavanadate and pyridoxalphosphate‐6‐azophenyl‐2',4′‐disulphonic acid (PPADS) showed that neither compound‐17 nor GW791343 competitively interacted at the ATP binding site and so were probably negative allosteric modulators of the P2X7receptor. GW791343 prevented the slowly reversible blockade of the human P2X7receptor produced by compound‐17 and inhibited [3H]‐compound‐17 binding to the P2X7receptor suggesting they may bind to similar or interacting sites. At rat P2X7receptors, compound‐17 was a negative allosteric modulator but the predominant effect of GW791343 was to increase agonist responses. Antagonist interaction and radioligand binding studies revealed that GW791343 did not interact at the ATP binding site but did interact with the compound‐17 binding site suggesting that GW791343 is a positive allosteric modulator of the rat P2X7receptor.Conclusions: Compound‐17 was a negative allosteric modulator of human and rat P2X7receptors. GW791343 was a negative allosteric modulator of the human P2X7receptor but at the rat P2X7receptor its predominant effect was positive allosteric modulation. These compounds should provide valuable tools for mechanistic studies on P2X7receptors.British Journal of Pharmacology(2008)153, 737–750; doi:10.1038/sj.bjp.0707625; published online 10 December 2007

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