title: Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X7receptor antagonists.
abstract: 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.
authors.affiliation: School of Chemistry, The University of Sydney, NSW, 2006, Australia.
authors.forename: James
authors.initials: J
authors.lastname: O'Brien-Brown
authors.affiliation: School of Medical Sciences, The University of Sydney, NSW, 2006, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Jackson
authors.affiliation: School of Chemistry, The University of Sydney, NSW, 2006, Australia.
authors.forename: Tristan A
authors.initials: TA
authors.lastname: Reekie
authors.affiliation: Faculty of Health Sciences, The University of Sydney, NSW, 2006, Australia.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Barron
authors.affiliation: Faculty of Health Sciences, The University of Sydney, NSW, 2006, Australia.
authors.forename: Eryn L
authors.initials: EL
authors.lastname: Werry
authors.affiliation: School of Chemistry, The University of Sydney, NSW, 2006, Australia.
authors.forename: Paolo
authors.initials: P
authors.lastname: Schiavini
authors.affiliation: School of Medical Sciences, The University of Sydney, NSW, 2006, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: McDonnell
authors.affiliation: Charles Perkins Centre, The University of Sydney, NSW, 2006, Australia.
authors.forename: Lenka
authors.initials: L
authors.lastname: Munoz
authors.affiliation: School of Chemistry, The University of Sydney, NSW, 2006, Australia.
authors.forename: Shane
authors.initials: S
authors.lastname: Wilkinson
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, SA, 5001, Australia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Noll
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, SA, 5001, Australia.
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
authors.affiliation: School of Chemistry, The University of Sydney, NSW, 2006, Australia. Electronic address: michael.kassiou@sydney.edu.au.
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
mesh_terms: D000218:Adamantane / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry* / Q000494:pharmacology; D001519:Behavior / Q000187:drug effects; D055808:Drug Discovery; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D058920:Purinergic P2X Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D006146:Guanidines; D058920:Purinergic P2X Receptor Antagonists; C004711:dicyandiamido; D000218:Adamantane
keywords: ATP; Adamantane; Adamantyl; Alzheimer's; IL-1β; Inflammation; Neurodegenerative; P2X receptor; P2X(7)R antagonist