Journal article Open Access

Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X7 receptor antagonists.

O'Brien-Brown, James; Jackson, Alexander; Reekie, Tristan A; Barron, Melissa L; Werry, Eryn L; Schiavini, Paolo; McDonnell, Michelle; Munoz, Lenka; Wilkinson, Shane; Noll, Benjamin; Wang, Shudong; Kassiou, Michael

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-1β 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 P2X7R antagonists.

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