title: Investigations of amide bond variation and biaryl modification in analogues of α7 nAChR agonist SEN12333.
abstract: Several lines of experimental evidence support the involvement of the α7 nAChR in schizophrenia and Alzheimer's disease. Modulators of the α7 nAChR have been extensively reviewed for the treatment of the cognitive deficits associated with these pathologies. SEN12333 represents a novel α7 nAChR agonist chemotype with potential for reduced side effects but requiring further SAR exploration. The present work investigates the amide bond of SEN12333, specifically its connectivity and replacement with the tetrazole functionality, a known cis amide isostere. The results reveal the original amide bond connectivity of SEN12333 to be favorable for binding affinity and agonist activity at α7 nAChRs. The use of a tetrazole isostere completely abolishes affinity and functional activity and suggests that SEN12333 binds in a linear conformation. Results reported herein also suggest the pyridine nitrogen within the terminal aromatic ring of SEN12333 is not essential for binding affinity or functional activity. Further SAR investigations involving manipulation of other moieties contained within SEN12333 are warranted.
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Corinne
authors.initials: C
authors.lastname: Beinat
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Tristan
authors.initials: T
authors.lastname: Reekie
authors.affiliation: School of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Hibbs
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20057, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Xie
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20057, USA.
authors.forename: Thao T
authors.initials: TT
authors.lastname: Olson
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20057, USA.
authors.forename: Yingxian
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Bionomics Limited, Thebarton, SA 5031, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Harvey
authors.affiliation: Bionomics Limited, Thebarton, SA 5031, Australia.
authors.forename: Susan
authors.initials: S
authors.lastname: O'Connor
authors.affiliation: Bionomics Limited, Thebarton, SA 5031, Australia.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Coles
authors.affiliation: CSIRO Materials Science & Engineering, Ian Wark Laboratory, Bayview Avenue, Clayton Victoria 3168, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Tsanaktsidis
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia; Discipline of Medical Radiation Sciences, The University of Sydney, Sydney, NSW 2006, Australia; Brain and Mind Research Institute, Sydney, NSW 2050, Australia. Electronic address: michael.kassiou@sydney.edu.au.
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
mesh_terms: D000577:Amides / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*
chemical_list: C540749:5-morpholin-4-ylpentanoic acid (4-pyridin-3-ylphenyl)amide; D000577:Amides; D009025:Morpholines; D018722:Nicotinic Agonists; D011725:Pyridines; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: AChR; Acetylcholine receptor; CNS; Isostere; Structure–activity relationships; Tetrazole; α(7) nicotinic receptors