The α7 nicotinic acetylcholine receptor (nAChR) silent agonists, able to induce receptor desensitization and promote the α7 metabotropic function, are emerging as new promising therapeutic anti-inflammatory agents. Herein, we report the structure–activity relationship investigation of the archetypal silent agonist NS6740 (1,4-diazabicyclo[3.2.2]nonan-4-yl(5-(3-(trifluoromethyl)-phenyl)-furan-2-yl)methanone) (1) to elucidate the ligand-receptor interactions responsible for the α7 silent activation. In this study, NS6740 fragments 11–16 and analogs 17–32 were designed, synthesized, and assayed on human α7 nAChRs expressed in Xenopus laevis oocytes with two-electrode voltage clamping experiments. All together the structural portions of NS6740 were critical to engender its peculiar activity profile. The diazabicyclic nucleus was essential but not sufficient for inducing α7 silent activation. The central hydrogen-bond acceptor core and the aromatic moiety were crucial for promoting prolonged α7 receptor binding and sustained desensitization. Compounds 13 and 17 were efficacious partial agonists. Compounds 12, 21, 23–26, and 30 strongly desensitized α7 nAChR and therefore may be of interest for additional investigation of inflammation responses. We gained key structural information useful for further silent agonist development.

Design, synthesis, and electrophysiological evaluation of NS6740 derivatives: Exploration of the structure-activity relationship for alpha7 nicotinic acetylcholine receptor silent activation / M.C. Pismataro, N.A. Horenstein, C. Stokes, M. Quadri, M. De Amici, R.L. Papke, C. Dallanoce. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 205(2020 Nov 01). [10.1016/j.ejmech.2020.112669]

Design, synthesis, and electrophysiological evaluation of NS6740 derivatives: Exploration of the structure-activity relationship for alpha7 nicotinic acetylcholine receptor silent activation

Pismataro M. C.;Quadri M.;De Amici M.;Dallanoce C.
2020-11-01

Abstract

The α7 nicotinic acetylcholine receptor (nAChR) silent agonists, able to induce receptor desensitization and promote the α7 metabotropic function, are emerging as new promising therapeutic anti-inflammatory agents. Herein, we report the structure–activity relationship investigation of the archetypal silent agonist NS6740 (1,4-diazabicyclo[3.2.2]nonan-4-yl(5-(3-(trifluoromethyl)-phenyl)-furan-2-yl)methanone) (1) to elucidate the ligand-receptor interactions responsible for the α7 silent activation. In this study, NS6740 fragments 11–16 and analogs 17–32 were designed, synthesized, and assayed on human α7 nAChRs expressed in Xenopus laevis oocytes with two-electrode voltage clamping experiments. All together the structural portions of NS6740 were critical to engender its peculiar activity profile. The diazabicyclic nucleus was essential but not sufficient for inducing α7 silent activation. The central hydrogen-bond acceptor core and the aromatic moiety were crucial for promoting prolonged α7 receptor binding and sustained desensitization. Compounds 13 and 17 were efficacious partial agonists. Compounds 12, 21, 23–26, and 30 strongly desensitized α7 nAChR and therefore may be of interest for additional investigation of inflammation responses. We gained key structural information useful for further silent agonist development.
a7 nicotinic acetylcholine receptor; Electrophysiology; Silent agonist; Partial agonist; 1,4-Diazabicyclo[3.2.2]nonane; Structure-activity relationship (SAR)
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/14 - Farmacologia
28-lug-2020
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Article (author)
File in questo prodotto:
File Dimensione Formato  
Eur.J.Med.Chem. 2020, 205, 112669.pdf

non disponibili

Tipologia: Publisher's version/PDF
Dimensione 3.36 MB
Formato Adobe PDF
3.36 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Postprint_Manuscript Dallanoce_Eur. J. Med. Chem. 2020.pdf

accesso aperto

Tipologia: Pre-print (manoscritto inviato all'editore)
Dimensione 1.63 MB
Formato Adobe PDF
1.63 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/768482
Citazioni
  • ???jsp.display-item.citation.pmc??? 3
  • Scopus 7
  • ???jsp.display-item.citation.isi??? 7
social impact