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EnglishThe 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).
| Titolo: | Design, synthesis, and electrophysiological evaluation of NS6740 derivatives: Exploration of the structure-activity relationship for alpha7 nicotinic acetylcholine receptor silent activation |
| Autori: | PISMATARO, MARIA CHIARA (Primo) DALLANOCE, CLELIA MARIANGIOLA LUISA (Ultimo) (Corresponding) |
| Parole Chiave: | a7 nicotinic acetylcholine receptor; Electrophysiology; Silent agonist; Partial agonist; 1,4-Diazabicyclo[3.2.2]nonane; Structure-activity relationship (SAR) |
| Settore Scientifico Disciplinare: | Settore CHIM/08 - Chimica Farmaceutica Settore BIO/14 - Farmacologia |
| Data di pubblicazione: | 1-nov-2020 |
| Rivista: | |
| Tipologia: | Article (author) |
| Data ahead of print / Data di stampa: | 28-lug-2020 |
| Digital Object Identifier (DOI): | http://dx.doi.org/10.1016/j.ejmech.2020.112669 |
| Appare nelle tipologie: | 01 - Articolo su periodico |
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| File | Descrizione | Tipologia | Licenza | |
|---|---|---|---|---|
| Eur.J.Med.Chem. 2020, 205, 112669.pdf | Publisher's version/PDF | Administrator Richiedi una copia | ||
| Postprint_Manuscript Dallanoce_Eur. J. Med. Chem. 2020.pdf | Pre-print (manoscritto inviato all'editore) | Open Access Visualizza/Apri |
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