Mechanism of action of species-selective P2X7 receptor antagonists

摘要: Background and purpose:  AZ11645373 N-{2-methyl-5-[(1R, 5S)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylcarbonyl]phenyl}-2-tricyclo[3.3.1.13,7]dec-1-ylacetamide hydrochloride (compound-22) are recently described P2X7 receptor antagonists. In this study we have further characterized these compounds to determine their mechanism of action interaction with other species orthologues. Experimental approach:  Antagonist effects at recombinant chimeric receptors were assessed by ethidium accumulation radioligand-binding studies. Key results:  compound-22 confirmed as selective non-competitive antagonists human or rat respectively. Both weak the mouse guinea-pig and, for each compound, potency estimates dog similar. The was moderately temperature-dependent while that not. antagonist both slowly reversible not prevented decavanadate, suggesting they allosteric Indeed, competed binding sites labelled an radio-labelled antagonist. selectivity AZ11645373, but compound-22, influenced nature amino acid position 95 receptor. N2-(3,4-difluorophenyl)-N1-[2-methyl-5-(1-piperazinylmethyl)phenyl]glycinamide dihydrochloride, a positive modulator receptor, reduced had little effect on actions AZ11645373. Conclusions:  differential two suggests there may be more than one regulatory site which can bind affect function.