Investigations of amide bond variation and biaryl modification in analogues of α7 nAChR agonist SEN12333

Corinne Beinat; Tristan Reekie; David Hibbs; Teresa Xie; Thao T Olson; Yingxian Xiao; Andrew Harvey; Susan O'Connor; Carolyn Coles; John Tsanaktsidis; Michael Kassiou

doi:10.1016/j.ejmech.2014.07.029

Investigations of amide bond variation and biaryl modification in analogues of α7 nAChR agonist SEN12333

Eur J Med Chem. 2014 Sep 12:84:200-5. doi: 10.1016/j.ejmech.2014.07.029. Epub 2014 Jul 9.

Authors

Affiliations

¹ School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
² School of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.
³ Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20057, USA.
⁴ Bionomics Limited, Thebarton, SA 5031, Australia.
⁵ CSIRO Materials Science & Engineering, Ian Wark Laboratory, Bayview Avenue, Clayton Victoria 3168, Australia.
⁶ 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.

PMID: 25019477
DOI: 10.1016/j.ejmech.2014.07.029

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.

Keywords: AChR; Acetylcholine receptor; CNS; Isostere; Structure–activity relationships; Tetrazole; α(7) nicotinic receptors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amides / chemistry*
Dose-Response Relationship, Drug
Humans
Models, Molecular
Molecular Structure
Morpholines / chemical synthesis
Morpholines / chemistry*
Morpholines / pharmacology*
Nicotinic Agonists / chemical synthesis
Nicotinic Agonists / chemistry*
Nicotinic Agonists / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / pharmacology*
Structure-Activity Relationship
alpha7 Nicotinic Acetylcholine Receptor / agonists*

Substances

5-morpholin-4-ylpentanoic acid (4-pyridin-3-ylphenyl)amide
Amides
Morpholines
Nicotinic Agonists
Pyridines
alpha7 Nicotinic Acetylcholine Receptor