Identification of regions of the P2X7 receptor that contribute to human and rat species differences in antagonist effects

摘要: Background and purpose: Several P2X7 receptor antagonists are allosteric inhibitors exhibit species difference in potency. Furthermore, N2-(3,4-difluorophenyl)-N1-(2-methyl-5-(1-piperazinylmethyl)phenyl)glycinamide dihydrochloride (GW791343) exhibits negative effects at the human but is a positive modulator of rat receptor. In this study we have identified several regions that contribute to differences antagonist effects. Experimental approach: Chimeric human-rat receptors were constructed with being inserted into Antagonist these measured ethidium accumulation radioligand binding studies. Key results: Exchanging close transmembrane domain 1 modified KN62, 4-(4-fluorophenyl)-2-(4-methylsulphinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) GW791343. Further studies, which single amino acids exchanged, acid 95 as primarily responsible for differential GW791343 and, varying degrees, potency SB203580 KN62. The selectivity pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic was affected by multiple receptor, particularly 126 not 95. A further region (amino 154–183) that, when corresponding position increased ATP 10-fold. Conclusions: This has key residues also can significantly affect agonist receptor. British Journal Pharmacology (2008) 155, 738–751; doi:10.1038/bjp.2008.306; published online 28 July 2008