Antinociceptive and anticonvulsant effects of the monoterpene linalool oxide.

CONTEXT: Linalool oxide (OXL) (a monoterpene) is found in the essential oils of certain aromatic plants, or it is derived from linalool. The motivation for this work is the lack of psychopharmacological studies on this substance. OBJECTIVE: To evaluate OXL's acute toxicity, along with its anticonvulsant and antinociceptive activities in male Swiss mice. MATERIAL AND METHODS: OXL (50, 100 and 150 mg/kg, i.p.) was investigated for acute toxicity and in the Rota-rod test. Antinociceptive activity was evaluated by the acetic acid-induced writhing test, and by formalin testing. Anticonvulsant effects were demonstrated by testing for pentylenetetrazol (PTZ)-induced seizures and by Maximum Electroshock headset (MES) test. OXL was administered to the animals intraperitoneally 30 min before for pharmacological tests. RESULTS: OXL showed an LD50 of ∼721 (681-765) mg/kg. In the Rota-rod test, it was observed that OXL caused no damage to the animal's motor coordination. OXL significantly reduced (p < .001) the number of writhings. OXL also significantly decreased (p < .05, p < .01 or p < .001) paw-licking time in the two phases of the formalin test. OXL significantly reduced (p < .01 or p < .001) the duration of tonic seizures in the MES test, and at the dose 150 mg/kg, significantly increased (p < .01) the latency to first seizure in the PTZ test. CONCLUSION: The tested doses of OXL were safe, with no motor impairment, and show clear antinociceptive and anticonvulsant potential. Future investigations with this monoterpene may lead to the development of a new molecule with even higher potency and selectivity.

Triphenylmethane derivatives have high in vitro and in vivo activity against the main causative agents of cutaneous leishmaniasis.

The current standard of care for cutaneous leishmaniasis (CL) is organic antimonial compounds, but the administration of these compounds is complicated by a low therapeutic - toxic index, as well as parenteral administration. Thus, there is an urgent need for the development of new and inexpensive therapies for the treatment of CL. In this study, we evaluate the activity of the triphenylmethane (TPM) class of compounds against three species of Leishmania which are pathogenic in humans. The TPM have a history of safe use in humans, dating back to the use of the original member of this class, gentian violet (GV), from the early 20(th) century. Initially, the in vitro efficacy against Leishmania (Viannia) braziliensis, L. (Leishmania) amazonensis and L. (L.) major of 9 newly synthesized TPM, in addition to GV, was tested. Inhibitory concentrations (IC) IC(50) of 0.025 to 0.84 µM had been found in promastigotes in vitro assays. The four most effective compounds were then tested in amastigote intracellular assays, resulting in IC(50) of 0.10 to 1.59 µM. A high degree of selectivity of antiparasitic activity over toxicity to mammalian cells was observed. Afterwards, GV and TPM 6 were tested in a topical formulation in mice infected with L. (L.) amazonensis leading to elimination of parasite burdens at the site of lesion/infection. These results demonstrated that TPM present significant anti-leishmanial activities and provide a rationale for human clinical trials of GV and other TPM. TPM are inexpensive and safe, thus using them for treatment of CL may have a major impact on public health.

Genetic neural network modeling of the selective inhibition of the intermediate-conductance Ca2+ -activated K+ channel by some triarylmethanes using topological charge indexes descriptors.

Selective inhibition of the intermediate-conductance Ca(2+)-activated K(+ )channel (IK (Ca)) by some clotrimazole analogs has been successfully modeled using topological charge indexes (TCI) and genetic neural networks (GNNs). A neural network monitoring scheme evidenced a highly non-linear dependence between the IK (Ca) blocking activity and TCI descriptors. Suitable subsets of descriptors were selected by means of genetic algorithm. Bayesian regularization was implemented in the network training function with the aim of assuring good generalization qualities to the predictors. GNNs were able to yield a reliable predictor that explained about 97% data variance with good predictive ability. On the contrary, the best multivariate linear equation with descriptors selected by linear genetic search, only explained about 60%. In spite of when using the descriptors from the linear equations to train neural networks yielded higher fitted models, such networks were very unstable and had relative low predictive ability. However, the best GNN BRANN 2 had a Q ( 2 ) of LOO of cross-validation equal to 0.901 and at the same time exhibited outstanding stability when calculating 80 randomly constructed training/test sets partitions. Our model suggested that structural fragments of size three and seven have relevant influence on the inhibitory potency of the studied IK (Ca) channel blockers. Furthermore, inhibitors were well distributed regarding its activity levels in a Kohonen self-organizing map (KSOM) built using the inputs of the best neural network predictor.

Understanding channel blocking in the nicotinic acetylcholine receptor.

Ion-channel blockers are molecules that obstruct the path used by ions to cross the membrane through a protein channel. Many of these are local anesthetics, toxins or drugs of abuse, and the knowledge of their mechanism of action at the atomic level is an important step towards the development of new compounds on a structural basis. A molecular model of the transmembrane region of the nicotinic acetylcholine receptor, an important brain and muscle fast signaling protein, was used as a target for docking several channel blockers by means of an automatic docking method. The combination of the independent docking method and molecular models (of the receptor and blockers) reproduced or explained quite accurately experimental data (photoaffinity labeling, site-directed mutagenesis, binding assays). This represents a strong support for the validity of the predictions made for those molecules for which no experimental data is available and also for the models and methods on which are based.

[The role of hyperpolarization and depolarization of the membrane of the human spermatozoon]. / Papel de la hiperpolarización y despolarización en la membrana del espermatozoide humano.

The electric potential across the membrane (psi) is evaluated through the accumulation of the lipophilic, radiolabelled, triphenylmethylphosphonium (3H-TPMP+), cation on membrane human sperm. The washed sperm cells, were incubated in presence of 3H-TPMP+ in low-K+ medium or high-K+ and allowed to take up the cation to steady-state (ie; 20 min at 37 degrees C). By using this differential, the value obtained was inserted in the Nernst equation, this value yielded a psi of -69 +/- 2 mV. The presence of divalent cations Zn++ and Mg++ in the incubation medium both induced a hyperpolarization of 10% and 8.6%, respectively. The addition of specific reagents such as p-chloromercuribenzene-sulfonate and ethylene-diamine-tetraacetic acid sodium salt both decreased the psi 35% and 58% respectively. The agents to act upon the components of the sperm cell membrane such as the dithiothreitol and progesterone induced hyperpolarization and depolarization of the membrane 16% and 40%, respectively. The presence of propranolol and L-alpha-lysophosphatidylcholine, which affect the ionic gradients present across the plasma membrane, both induced a depolarization from 43% and 92% respectively. Finally, the addition of tetraphenylboron (TPB-) on the incubation medium, enhanced the value of the psi 75%. These studies are transcendent because with the utilization of agents depolarizing, or hyperpolarizing we obtain changes in the psi from -80 +/- 0.6 mV, until -6 +/- 0.6 mV changes of 74 +/- 1.5 mV across of the sperm cell membrane.