title: Inhibitory activities on mammalian central nervous system receptors and computational studies of three sesquiterpene lactones from Coriaria ruscifolia subsp. ruscifolia.
abstract: The electrophysiological characterization of sesquiterpene lactones from Coriaria ruscifolia subsp. ruscifolia has been tested on hippocampal neurons. The results for glycinergic rat hippocampal transmission and native γ-aminobutyric acid (GABA)ergic transmission on neurons (13DIV) are remarkably different for tutin, coriamyrtin, and dihydrotutin, being tutin the most potent inhibitor and dihydrotutin the least potent one. To understand the applied mechanism of action, we discuss the structural and electronic requirements for inhibitory activity by these sesquiterpene lactones when modulating receptors of the central nervous system. The structural and electrostatic properties of these compounds were compared to those of more active metabolites like picrotoxins. The minimal energy level of these structures was calculated and then optimized at the ab initio B3LYP/DGDZVP level of theory using Gaussian 03W software. This allowed calculation of the corresponding vibrational circular dichroism spectrum of coriamyrtin which rendered the molecular absolute configuration after comparison with an experimental spectrum. These results are consistent with those from studies of other models that provide the basis for the activity on the presence of the lactone at carbons 3 and 5, the presence of the hydroxyl group at position 6, and the different electronic distributions observed in tutin and coriamyrtin. The latter has an isopropenyl moiety at carbon 4 in contrast to the dihydrotutin isopropyl group at the same position, which could explain the difference in activity between dihydrotutin and tutin or coriamyrtin. The presence of the hydroxyl group at carbon 2 is not decisive since this functionality is present in tutin, the most active compound, and in dihydrotutin, the less active one.
authors.affiliation: Laboratoria de Química de Productos Naturales, Departamento de Botánica, Facultad de Ciencias Naturales y Oceanográficas, Universidad de Concepción, Concepción, Chile. claudiaperez@udec.cl
authors.forename: Claudia
authors.initials: C
authors.lastname: Pérez
authors.forename: José
authors.initials: J
authors.lastname: Becerra
authors.forename: Paula
authors.initials: P
authors.lastname: Manríquez-Navarro
authors.forename: Luis Gerardo
authors.initials: LG
authors.lastname: Aguayo
authors.forename: Jorge
authors.initials: J
authors.lastname: Fuentealba
authors.forename: José Leonardo
authors.initials: JL
authors.lastname: Guzmán
authors.forename: Pedro
authors.initials: P
authors.lastname: Joseph-Nathan
authors.forename: Verónica
authors.initials: V
authors.lastname: Jiménez
authors.forename: Marcelo Andrés
authors.initials: MA
authors.lastname: Muñoz
authors.forename: Mario
authors.initials: M
authors.lastname: Silva
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects / Q000502:physiology; D019295:Computational Biology / Q000379:methods; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D010852:Picrotoxin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000502:physiology; D018079:Receptors, GABA / Q000502:physiology; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014961:X-Ray Diffraction
chemical_list: D007783:Lactones; D010852:Picrotoxin; D018160:Receptors, Cytoplasmic and Nuclear; D018079:Receptors, GABA; D012717:Sesquiterpenes; C000510:coriamyrtine; C009614:tutin