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

Primer Autor
Paz, Cristian
Co-autores
Ernesto Ottone, Nicolas#Baptista, Carlos A. C.#Latorre, Rafael#Felipe Bianchi, Homero#Del Sol, Mariano
Título
Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 Subtypes
Editorial
AMER CHEMICAL SOC
Revista
JOURNAL OF NATURAL PRODUCTS
Lenguaje
en
Resumen
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 h alpha 4 beta 2, h alpha 3 beta 4, and h alpha 7 nicotinic acetylcholine receptors (AChRs) by Ca2+ influx measurements. The results established that drimane sesquiterpenoids inhibit AChRs with the following selectivity: h alpha 4 beta 2 > h alpha 3 beta 4 > h alpha 7. In the case of h alpha 4 beta 2 AChRs, the following potency rank order was determined (IC50's in mu M): 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 h alpha 4 beta 2 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-beta 2 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 h alpha 4 beta 2 AChR by a cooperative mechanism, as shown experimentally (n(H) > 1). Drimenin could be used as a molecular scaffold for the development of more potent inhibitors with higher selectivity for the h alpha 4 beta 2 AChR.
Tipo de Recurso
Artículo original
Description
This study was supported by grants from the Universidad de La Frontera (DI17-0049), REDI170107 from CONICYT (to C.P.), and California Northstate University College of Medicine (to H.RA.).
Este estudio fue apoyado por subvenciones de la Universidad de La Frontera (DI17-0049), REDI170107 de CONICYT (a C.P.) y California Northstate University College of Medicine (a H.RA.).
doi
10.1021/acs.jnatprod.7b00893
Formato Recurso
pdf
Ubicación del archivo
http://dx.doi.org/10.1021/acs.jnatprod.7b00893
Categoría OCDE
Plant Sciences# Chemistry, Medicinal# Pharmacology & Pharmacy
Disciplinas de la OCDE
Farmacología y Farmacia
Química Orgánica
Neurociencias
Id de Web of Science
WOS:000431165100011
Título de la cita (Recomendado-único)
Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 Subtypes
Identificador relacionado
hdl.handle.net/11336/72261
Identificador del recurso (Mandatado-único)
Artículo original
Versión del recurso (Recomendado-único)
version publicada
Editorial
AMER CHEMICAL SOC
Revista/Libro
JOURNAL OF NATURAL PRODUCTS
Categoría WOS
Ciencias Vegetales# Química Medicinal# Farmacología y farmacia
ISSN
0163-3864
Idioma
en
Referencia del Financiador (Mandatado si es aplicable-repetible)
UFRO DI17-0049#ANID CONICYT REDI170107
UFRO DI17-0049
ANID CONICYT REDI170107
California Northstate University College of Medicine
Descripción
This study was supported by grants from the Universidad de La Frontera (DI17-0049), REDI170107 from CONICYT (to C.P.), and California Northstate University College of Medicine (to H.RA.).
Formato
pdf
Tipo de ruta
hibrida
Access Rights
metadata
Derechos de acceso
metadata
Página de inicio (Recomendado-único)
885
Página final (Recomendado-único)
893
Colecciones
Colección Publicaciones Científicas
Revisa las metricas alternativas de Almetrics
Revisa las citaciones de Dimensions