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Identification of α7 Nicotinic Acetylcholine Receptor Silent Agonists Based on the Spirocyclic Quinuclidine-Δ 2 -Isoxazoline Scaffold: Synthesis and Electrophysiological Evaluation.

Authors :
Quadri M
Matera C
Silnović A
Pismataro MC
Horenstein NA
Stokes C
Papke RL
Dallanoce C
Source :
ChemMedChem [ChemMedChem] 2017 Aug 22; Vol. 12 (16), pp. 1335-1348. Date of Electronic Publication: 2017 Jun 12.
Publication Year :
2017

Abstract

Compound 11 (3-(benzyloxy)-1'-methyl-1'-azonia-4H-1'-azaspiro[isoxazole-5,3'-bicyclo[2.2.2]octane] iodide) was selected from a previous set of nicotinic ligands as a suitable model compound for the design of new silent agonists of α7 nicotinic acetylcholine receptors (nAChRs). Silent agonists evoke little or no channel activation but can induce the α7 desensitized D <subscript>s</subscript> state, which is sensitive to a type II positive allosteric modulator, such as PNU-120596. Introduction of meta substituents into the benzyloxy moiety of 11 led to two sets of tertiary amines and quaternary ammonium salts based on the spirocyclic quinuclidinyl-Δ <superscript>2</superscript> -isoxazoline scaffold. Electrophysiological assays performed on Xenopus laevis oocytes expressing human α7 nAChRs highlighted four compounds that are endowed with a significant silent-agonism profile. Structure-activity relationships of this group of analogues provided evidence of the crucial role of the positive charge at the quaternary quinuclidine nitrogen atom. Moreover, the present study indicates that meta substituents, in particular halogens, on the benzyloxy substructure direct specific interactions that stabilize a desensitized conformational state of the receptor and induce silent activity.<br /> (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Details

Language :
English
ISSN :
1860-7187
Volume :
12
Issue :
16
Database :
MEDLINE
Journal :
ChemMedChem
Publication Type :
Academic Journal
Accession number :
28494140
Full Text :
https://doi.org/10.1002/cmdc.201700162