Inhibitory Activities on Mammalian Central Nervous System Receptors and Computational Studies of Three Sesquiterpene Lactones from Coriaria ruscifolia subsp. ruscifolia

Abstract

Regular ArticleThe picrotoxin-like sesquiterpene lactones found in Anamirta paniculata and A. cocculus have generated longstanding theoretical interest, with early studies done in the 1960s and 1970s, to understand their mode of anticonvulsive action as potent transmission inhibitors in the central nervous system. The presence of an unusual carbon skeleton in the picrotoxin group of sesquiterpenes and in structurally related compounds generated crystallographic, biogenetic and conformational studies. Since then subsequent works have contributed to the study of many diseases associated to the central nervous system.The parameters used in the first structure-activity study of picrotoxins were media convulsive dose (CD 50 ) and LD 50 . The active compounds posses a lactone ring joining the C-3 and C-5 atoms (see 1), a tertiary hydroxyl group at C-6, and an isopropenyl group at C-4 (Chart 1). The study allowed selection of the active compounds and determined that the existence of the hydroxyl group, the lactone ring and the axial isopropenyl group played a determinant role in the activity on the central nervous system, although picrotoxin activity was not tested at the presynaptic inhibitory synapse level of the central nervous system. 1)The results of the assessment of picrotoxinin and related compounds activity, specifically picrotin, tutin (1), and coriamyrtin (2) on frog spinal cords were published twenty years later. The conclusions suggested that the presence of a hydroxyl group at C-6 could have a significant affinity for a gaminobutyric acid (GABA) effector chloride channel, an antagonist to the effects observed on g-aminobutyric acid but not on alanine or taurine. These experiments were tested on primary afferent terminals and for the antagonism of presynaptic inhibition. 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 g gaminobutyric 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...

Antimicrobial evaluation of Huilliche plant medicine used to treat wounds

“…Also from fruits, ellagic acid 3,3 -dimethylether and corianin were obtained, but they only showed scant antibacterial activity, and likewise, only moderate cytotoxicity. These results were not conclusive with regard to the properties attributed to the fruits (Valencia et al, 2001), but the findings of tutin and coriamyrtin (Reyes et al, 1980) in the fruits indicate that these two and probably other sesquiterpene lactones are responsible for the activity observed (Perez et al, 2011). However, the active constituents of leaves and stem still have to be confirmed, since the sesquiterpene lactones are only reported from the fruits.…”

Picrotoxane sesquiterpenoids: chemistry, chemo- and bio-syntheses and biological activities

“…1 Its structure was nally proved by Opticalrotatory Dispersion (ORD) spectroscopy, 34 1D NMR 35 and X-ray diffraction analysis. 36 Subsequently, coriamyrtin was also found to be the major toxic constituent of some other Coriariaceae species, such as C. japonica, 35 C. ruscifolia, [37][38][39] C. nepalensis ¼ C. sinica, 40,41 C. microphylla ¼ C. thymifolia 42,43 and C. intermedia, 44 as well as Loranthaceae species (L. parasiticus). 45 Tutin (18) was rst found in C. ruscifolia, C. microphylla and C. augustissima, as a bitter and toxic lactone.…”

“…The research results for GABAergic transmission through neurons were signicantly different for tutin (18), coriamyrtin (17), and dihydrotutin (21), and the structure-activity relationship revealed that the presence of 5,3-g-lactone and 6-hydroxyl group, as well as the 4-isopropenyl moiety, were essential for the inhibitory activities, whereas the 2-hydroxyl group was not decisive. 39 GABA receptor antagonists include structurally quite distinct compounds (such as a-endosulphan, lindane, pronil, and picrotoxinin), and surprisingly, these small molecules appear to bind to the same site. Some researchers have explained the general structural features, steric congurations and electrostatic elds required to generate similar antagonistic effects at the GABA receptor.…”

“…The research results for GABAergic transmission through neurons were significantly different for tutin ( 18 ), coriamyrtin ( 17 ), and dihydrotutin ( 21 ), and the structure–activity relationship revealed that the presence of 5,3-γ-lactone and 6-hydroxyl group, as well as the 4-isopropenyl moiety, were essential for the inhibitory activities, whereas the 2-hydroxyl group was not decisive. 39…”

Solid State Structure and Absolute Configuration of Filifolinol Acetate

“…Filifolinol acetate ( 4) is a good candidate for vibrational circular dichroism (VCD) studies since, due to its rigid molecular structure, a small number of final conformers can be anticipated, thereby simplifying the overall density functional theory (DFT) calculations. In fact, the VCD methodology has proved to be very powerful to establish the absolute configuration of natural products [7], in particular for the study of rigid mono- [8,9] and sesquiterpenes [10,11]. Thus, the absolute configuration of 4 was determined from a study in which the experimental spectrum was compared with the theoretical curve obtained by DFT calculation at the B3LYP/DGDZVP level of theory.…”