Here we report adamantyl cyanoguanidine compounds based on hybrids of the adamantyl amide scaffold reported by AstraZeneca and cyanoguanidine scaffold reported by Abbott Laboratories. Compound 27 displayed five-fold greater inhibitory potency than the lead compound 2 in both pore-formation and interleukin-1 beta release assays, while 35-treated mice displayed an antidepressant phenotype in behavioral studies. This SAR study provides a proof of concept for hybrid compounds, which will help in the further development of P2X(7)R antagonists. (C) 2017 Elsevier Masson SAS. All rights reserved.