Structure-activity relationship studies of SEN12333 analogues: determination of the optimal requirements for binding affinities at α7 nAChRs through incorporation of known structural motifs

Corinne Beinat; Tristan Reekie; Samuel D Banister; James O'Brien-Brown; Teresa Xie; Thao T Olson; Yingxian Xiao; Andrew Harvey; Susan O'Connor; Carolyn Coles; Anton Grishin; Peter Kolesik; John Tsanaktsidis; Michael Kassiou

doi:10.1016/j.ejmech.2015.03.025

Structure-activity relationship studies of SEN12333 analogues: determination of the optimal requirements for binding affinities at α7 nAChRs through incorporation of known structural motifs

Eur J Med Chem. 2015 May 5:95:277-301. doi: 10.1016/j.ejmech.2015.03.025. Epub 2015 Mar 14.

Authors

Affiliations

¹ School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia; Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
² School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
³ Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁴ Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20057, USA.
⁵ Bionomics Limited, Thebarton, SA 5031, Australia.
⁶ CSIRO Materials Science & Engineering, Ian Wark Laboratory, Bayview Avenue, Clayton, Victoria 3168, Australia.
⁷ School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia; Faculty of Health Sciences, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: michael.kassiou@sydney.edu.au.

PMID: 25827398
DOI: 10.1016/j.ejmech.2015.03.025

Abstract

Alpha7 nicotinic acetylcholine receptors (nAChRs) have implications in the regulation of cognitive processes such as memory and attention and have been identified as a promising therapeutic target for the treatment of the cognitive deficits associated with schizophrenia and Alzheimer's disease (AD). Structure affinity relationship studies of the previously described α7 agonist SEN12333 (8), have resulted in the identification of compound 45, a potent and selective agonist of the α7 nAChR with enhanced affinity and improved physicochemical properties over the parent compound (SEN12333, 8).

Keywords: Acetylcholine receptor; CNS; Structure–activity relationships; α7 nicotinic receptors.

Publication types

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

MeSH terms

Drug Discovery*
Electrophysiological Phenomena / drug effects
HEK293 Cells
Humans
Models, Molecular
Morpholines / chemistry*
Morpholines / metabolism*
Morpholines / pharmacology
Protein Binding
Protein Conformation
Pyridines / chemistry*
Pyridines / metabolism*
Pyridines / pharmacology
Structure-Activity Relationship
alpha7 Nicotinic Acetylcholine Receptor / chemistry
alpha7 Nicotinic Acetylcholine Receptor / metabolism*

Substances

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