Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 Subtypes

Authors
Arias, Hugo Rubén; Feuerbach, Dominik; Schmidt, Bernd; Heydenreich, Matthias; Paz, Cristian; Ortells, Marcelo Oscar
Publication Year
2018
Language
English
Format
article
Status
Published version
Description
The drimane sesquiterpenoids drimenin, cinnamolide, dendocarbin A, and polygodial were purified from the Canelo tree (Drimys winteri) and chemically characterized by spectroscopic methods. The pharmacological activity of these natural compounds were determined on hα4β2, hα3β4, and hα7 nicotinic acetylcholine receptors (AChRs) by Ca2+ influx measurements. The results established that drimane sesquiterpenoids inhibit AChRs with the following selectivity: hα4β2 > hα3β4 > hα7. In the case of hα4β2 AChRs, the following potency rank order was determined (IC50's in μM): drimenin (0.97 ± 0.35) > cinnamolide (1.57 ± 0.36) > polygodial (62.5 ± 19.9) dendocarbin A (no activity). To determine putative structural features underlying the differences in inhibitory potency at hα4β2 AChRs, additional structure-activity relationship and molecular docking experiments were performed. The Ca2+ influx and structural results supported a noncompetitive mechanism of inhibition, where drimenin interacted with luminal and nonluminal (TMD-β2 intrasubunit) sites. The structure-activity relationship results, i.e., the lower the ligand polarity, the higher the inhibitory potency, supported the nonluminal interaction. Ligand binding to both sites might inhibit the hα4β2 AChR by a cooperative mechanism, as shown experimentally (nH > 1). Drimenin could be used as a molecular scaffold for the development of more potent inhibitors with higher selectivity for the hα4β2 AChR.
Fil: Arias, Hugo Rubén. California Northstate University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; Suiza
Fil: Schmidt, Bernd. Universitat Potsdam; Alemania
Fil: Heydenreich, Matthias. Universitat Potsdam; Alemania
Fil: Paz, Cristian. Universidad de La Frontera; Chile
Fil: Ortells, Marcelo Oscar. Universidad de Morón; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Subject
NICOTINIC RECEPTOR
drimane sesquiterpenoids
INHIBITOR
Inmunología
Medicina Básica
CIENCIAS MÉDICAS Y DE LA SALUD
Access level
Restricted access
License
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/72261