Salvia divinorum (Lamiaceae) is a herb native to Mexico where it is used by Mazatec shamans for spiritual and divination purposes. S. divinorum products are easily available to consumers and are used worldwide as legal highs because of the hallucinogenic effects caused mainly by salvinorin A. Highly popular videos and websites on the internet depicting the use of S. divinorum products have contributed to an increase in their consumption. Recent reports have highlighted the potential of these products to induce psychosis in consumers. In Mexico, dried leaf extracts of S. divinorum are sold in different strengths, claiming to correlate with increasing amounts of salvinorin A. In order to determine the variability of salvinorin A content between brands and to investigate possible correlation between brand strengths, this study sought to quantify salvinorin A in commercial products available in Mexico using an HPLC method. The HPLC analytical method showed a correlation coefficient R(2)>0.99, with LOD of 0.44 μg/mL and LOQ of 1.34 μg/mL. The retention time for salvinorin A was 23.09±0.95 min and the measured concentrations ranged between 8.32±0.65 and 56.52±3.77 mg/g dried leaf. The results for brand c did not show an agreement between the declared and the calculated amount of salvinorin A. Additionally, the emergence in Mexico of high strength salvia products (100×), the lack of regulation and the observed variability of salvinorin A content between brands of commercial legal highs products of S. divinorum could result in a health problem for consumers.

Two series of isoindolines 1(a-g) and 2(a-g) were found by docking calculations to be possible L-type Ca(2+) channel (LCC) blockers. The theoretical 3-D model of the outer vestibule and the selective filter of the LCC was provided by Professor Lipkind; this model consists of transmembrane segments S5 and S6 and P-loops contributed by each of four repeats (I, II, III, and IV) of Ca(v) 1.2. Therefore, two well-known LCC blockers, nifedipine 3 and (R)-ethosuccinimide 4 were also evaluated, and their binding sites on the LCC were identified and compared with those obtained for 1(a-g) and 2(a-g). Analysis of the results shows that the target compounds tested probably could be LCC blockers, since they interact with or near the glutamic acid residues Glu393, Glu736, Glu1145 and Glu1446 (the EEEE locus), which belong to the LCC selectivity region. The G values for all of the Ca(2+) channel ligands are between-10.78 and -3.67 (kcal mol(-1)), showing that LCC-1b, -1e and -1f complexes are more stable than the other compounds tested. Therefore, theoretically calculated dissociation constants K(d) (microM) were obtained for all compounds. Comparing these values reveals that compounds 1b (0.0244 microM), 1e (0.0176 microM) and 1f (0.0125 microM) exhibit more affinity for the LCC than the other compounds. This screening shows that the two series of isoindolines probably could act as LCC blockers.

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Local reactivity is obtained for isatoic anhydride (ISA) (2H 3,1benzoxazin-2,4(1H)-dione) and 20 of its derivatives, using reactivity indices such as: local softness, condensed Fukui function, relative electrophilicity index, and relative nucleophilicity index. The local reactivity results for ISA show the best sites for a nucleophilic attack and for an electrophilic attack. A linear model is proposed from statistical methods to describe the substituent effect for the relationship between gas phase reactivity indices with respect to the Hammett constant values.

The aim of this study was to identify compounds that possess anticonvulsant activity by using a pentylenetetrazol (PTZ)-induced seizure model. Theoretical studies of a set of ligands, explored the binding affinities of the ligands for the GABA(A) receptor (GABA(A)R), including some benzodiazepines. The ligands satisfy the Lipinski rules and contain a pharmacophore core that has been previously reported to be a GABA(A)R activator. To select the ligands with the best physicochemical properties, all of the compounds were analyzed by quantum mechanics and the energies of the highest occupied molecular orbital and lowest unoccupied molecular orbital were determined. Docking calculations between the ligands and the GABA(A)R were used to identify the complexes with the highest Gibbs binding energies. The identified compound D1 (dibenzo(b,f)(1,4)diazocine-6,11(5H,12H)-dione) was synthesized, experimentally tested, and the GABA(A)R-D1 complex was submitted to 12-ns-long molecular dynamics (MD) simulations to corroborate the binding conformation obtained by docking techniques. MD simulations were also used to analyze the decomposition of the Gibbs binding energy of the residues involved in the stabilization of the complex. To validate our theoretical results, molecular docking and MD simulations were also performed for three reference compounds that are currently in commercial use: clonazepam (CLZ), zolpidem and eszopiclone. The theoretical results show that the GABA(A)R-D1, and GABA(A)R-CLZ complexes bind to the benzodiazepine binding site, share a similar map of binding residues, and have similar Gibbs binding energies and entropic components. Experimental studies using a PTZ-induced seizure model showed that D1 possesses similar activity to CLZ, which corroborates the predicted binding free energy identified by theoretical calculations.