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 alpha7 nicotinic acetylcholine receptors (nAChRs). Silent agonists evoke little or no channel activation but can induce the alpha7 desensitized Ds 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-Delta2-isoxazoline scaffold. Electrophysiological assays performed on Xenopus laevis oocytes expressing human alpha7 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.
Identification of α7 Nicotinic Acetylcholine Receptor Silent Agonists Based on the Spirocyclic Quinuclidine-Δ2-Isoxazoline Scaffold : Synthesis and Electrophysiological Evaluation / M. Quadri, C. Matera, A. Silnovic, M.C. Pismataro, N.A. Horenstein, C. Stokes, R.L. Papke, C. Dallanoce. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 12:16(2017 Aug 28), pp. 1335-1348.
|Titolo:||Identification of α7 Nicotinic Acetylcholine Receptor Silent Agonists Based on the Spirocyclic Quinuclidine-Δ2-Isoxazoline Scaffold : Synthesis and Electrophysiological Evaluation|
QUADRI, MARTA (Primo)
MATERA, CARLO (Secondo)
DALLANOCE, CLELIA MARIANGIOLA LUISA (Corresponding)
|Parole Chiave:||agonists; cycloaddition; nitrogen heterocycles; receptors; spiro compounds|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
Settore BIO/14 - Farmacologia
|Data di pubblicazione:||28-ago-2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1002/cmdc.201700162|
|Appare nelle tipologie:||01 - Articolo su periodico|