Iridoid esters from Valeriana pavonii Poepp. & Endl. as GABAA modulators: Structural insights in their binding mode and structure-activity relationship

Article published in J. Pharm. Pharmacogn. Res., vol. 11, no. 3, pp. 367-380, May-June 2023.

DOI: https://doi.org/10.56499/jppres22.1570_11.3.367

Original Article

Sara E. Giraldo^1,†, Mauricio Bedoya^2,3,†, Carlos Peña-Varas^4,5, Paula A. Santana⁶, Isabel L. Bazzocchi⁷, Ignacio A. Jiménez⁷, Mariel Marder⁸, Nadezdha E. Vergel⁹, Mario F. Guerrero⁹, David Ramírez^4*

¹Escuela de Ciencias Básicas y Aplicadas, Universidad de La Salle, 111711, Bogotá, Colombia.

²Centro de Investigación de Estudios Avanzados del Maule (CIEAM), Vicerrectoría de Investigación y Postgrado, Universidad Católica del Maule, Talca 3466706, Chile.

³Laboratorio de Bioinformática y Química Computacional (LBQC), Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Católica del Maule, Talca 3466706, Chile.

⁴Departamento de Farmacología, Facultad de Ciencias Biológicas, Universidad de Concepción. Concepción, Chile.

⁵Departamento de Ciencias de la Computación, Facultad de Ingeniería, Universidad de Concepción, Concepción, Chile.

⁶Facultad de Ingeniería, Instituto de Ciencias Químicas Aplicadas, Universidad Autónoma de Chile, Santiago, Chile.

⁷Instituto Universitario de Bio-Orgánica Antonio González, Departamento de Química Orgánica, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Canary Islands, Spain.

⁸Universidad de Buenos Aires. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Facultad de Farmacia y Bioquímica, Junín 956 (C1113AAD), Buenos Aires, Argentina.

⁹Departamento de Farmacia, Facultad de Ciencias, Universidad Nacional de Colombia, 111321, Bogotá, Colombia.

†These authors equally contributed to this work. *E-mail: dramirezs@udec.cl

Abstract

Context: Valeriana pavonii Poepp. & Endl. (Caprifoliaceae), is a plant used in traditional medicine as a tranquilizer in Colombia. Valerian extracts have been widely used since ancient times for their sedative and anxiolytic properties; however, the way its active metabolites, including iridoids, interact on their respective targets is not fully understood.

Aims: To isolate and identificate active iridoid esters from V. pavonii. Perform in vitro inhibition assays and computational analyses to study their possible interaction on the benzodiazepine site of the GABA_A receptor.

Methods: Two compounds were obtained from dichloromethane and petroleum ether fractions of V. pavonii, respectively, by chromatographic techniques. The structural elucidation was performed by NMR and spectroscopic analyses. In vitro inhibition assays of the binding of ³H-flunitrazepam (³H-FNZ) for the benzodiazepine binding site of the GABA_A receptor (BDZ-bs of the GABA_A receptor) were carried out.

Results: Two iridoid esters, hydrine-type valepotriates (compounds 1 and 2), were reported for the first time in V. pavonii. Both iridoids, 1 and 2, inhibited the binding of ³H-FNZ on the BDZ-bs of the GABA_A receptor (40% at 300 µM). Docking studies and MMGBSA calculations revealed that these compounds exhibited molecular interactions with crucial residues of the benzodiazepine site, similar to those observed for drugs like flunitrazepam, diazepam, and flumazenil.

Conclusions: These findings contribute to understanding the in vivo activity of extracts of Valeriana pavonni on the central nervous system, which showed promising effects, especially as anticonvulsants, sedative-hypnotics, and antidepressants, through the modulation of the GABAergic system by hydrine-type valepotriates and its derivatives.