ABSTRACT
In this investigation, we studied a family of compounds with an oxathiazolidine-4-one-2,2-dioxide skeleton and their amide synthetic precursors as new anticonvulsant drugs. The cyclic structures were synthesized using a three-step protocol that include solvent-free reactions and microwave-assisted heating. The compounds were tested in vivo through maximal electroshock seizure test in mice. All the structures showed activity at the lower doses tested (30 mg/Kg) and no signs of neurotoxicity were detected. Compound encoded as 1g displayed strong anticonvulsant effects in comparison with known anticonvulsants (ED50 = 29 mg/Kg). First approximations about the mechanisms of action of the cyclic structures were proposed by docking simulations and in vitro assays against sodium channels (patch clamp methods).
Subject(s)
Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Drug Design , Imides/chemistry , Imides/pharmacology , Thiazoles/chemistry , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/chemical synthesis , Carbon-13 Magnetic Resonance Spectroscopy , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Imides/chemical synthesis , Male , Mice , NAV1.1 Voltage-Gated Sodium Channel/drug effects , Oxides/chemistry , Patch-Clamp Techniques , Proton Magnetic Resonance SpectroscopyABSTRACT
Despite the introduction of more than 15 third generation antiepileptic drugs to the market from 1990 to the moment, about one third of the epileptic patients still suffer from refractory to intractable epilepsy. Several hypotheses seek to explain the failure of drug treatments to control epilepsy symptoms in such patients. The most studied one proposes that drug resistance might be related with regional overactivity of efflux transporters from the ATP-Binding Cassette (ABC) superfamily at the blood-brain barrier and/or the epileptic foci in the brain. Different strategies have been conceived to address the transporter hypothesis, among them inhibiting or down-regulating the efflux transporters or bypassing them through a diversity of artifices. Here, we review scientific evidence supporting the transporter hypothesis along with its limitations, as well as computer-assisted early recognition of ABC transporter substrates as an interesting strategy to develop novel antiepileptic drugs capable of treating refractory epilepsy linked to ABC transporters overactivity.
Subject(s)
ATP-Binding Cassette Transporters/metabolism , Computer-Aided Design , Drug Discovery/methods , Drug Resistant Epilepsy/drug therapy , Drug Resistant Epilepsy/metabolism , ATP-Binding Cassette Transporters/antagonists & inhibitors , Animals , HumansABSTRACT
We report herein the design and optimization of a novel series of sulfamides and sulfamates derived from amino esters with anticonvulsant properties. The structures were designed based on the pharmacophoric pattern previously proposed, with the aim of improving the anticonvulsant action. The compounds were obtained by a new synthetic procedure with microwave assisted heating and the use of adsorbents in the isolation process. All the derivatives showed protection against the maximal electroshock seizure test (MES test) in mice at the lowest dose tested (30 mg/kg) but they did not show significant protection against the chemical induced convulsion by pentylenetetrazole. These results verify the ability of the computational model for designing new anticonvulsants structures with anti-MES activity. Additionally, we evaluated the capacity of the synthesized structures to bind to the benzodiazepine binding site (BDZ-bs) of the γ-aminobutiric acid receptor (GABAA receptor). Some of them showed medium to low affinity for the BDZ-bs.
Subject(s)
Amides/chemistry , Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/pharmacology , Sulfonic Acids/chemical synthesis , Sulfonic Acids/pharmacology , Animals , Anticonvulsants/chemistry , Anticonvulsants/therapeutic use , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase Inhibitors/therapeutic use , Carbonic Anhydrases/chemistry , Carbonic Anhydrases/metabolism , Catalytic Domain , Chemistry Techniques, Synthetic , Esters , Male , Mice , Models, Molecular , Seizures/drug therapy , Sulfonic Acids/chemistry , Sulfonic Acids/therapeutic useABSTRACT
Steviol glycosides are natural constituents of Stevia rebaudiana (Bert.) Bert. (Asteraceae) that have recently gained worldwide approval as nonnutritive sweeteners by the Joint Food and Agriculture Organization/World Organization Expert Committee on Food Additives. Cheminformatic tools suggested that the aglycone steviol and several of its phase I metabolites were predicted as potential anticonvulsant agents effective in the seizure animal model maximal electroshock seizure (MES) test. Thus, aqueous infusion from S. rebaudiana was tested in the MES test (mice, intraperitoneal administration), confirming dose-dependent anticonvulsant effect. Afterward, isolated stevioside and rebaudioside A were tested in the MES test, with positive results. Though drug repositioning most often focuses on known therapeutics, this article illustrates the possibilities of this strategy to find new functionalities and therapeutic indications for food constituents and natural products.
Subject(s)
Anticonvulsants/pharmacology , Diterpenes, Kaurane/pharmacology , Glucosides/pharmacology , Non-Nutritive Sweeteners/pharmacology , Algorithms , Animals , Computational Biology , Computer Simulation , Dose-Response Relationship, Drug , Electroshock , High-Throughput Screening Assays , Mice , Models, Molecular , Seizures/drug therapy , Stevia/chemistry , Structure-Activity RelationshipABSTRACT
From a virtual screening campaign, a number of artificial and natural sweeteners were predicted as potential anticonvulsant agents with protective effects in the seizure animal model Maximal Electroshock Seizure (MES) test. In all cases, the predictions were experimentally confirmed in the aforementioned preclinical seizure model. The article reviews and expands previous reports from our group on anticonvulsant activity of those non-nutritive sweeteners, illustrating the potential of virtual screening approaches to propose new medical uses of food additives. This constitutes a particular case of knowledge-based drug repositioning, which may greatly shorten the development time and investment required to introduce novel medications to the pharmaceutical market. We also briefly overview evidence on possible molecular explanations on the anticonvulsant and proconvulsant effects of different non-nutritive sweeteners. Our analysis -based on Swanson's ABC model- suggests that group I metabotropic glutamate receptors and carbonic anhydrase isoform VII (both proposed or validated molecular targets of antiepileptic drugs) might be involved in the anticonvulsant effect of artificial sweeteners. The first hypothesis is in line with recent advances on development of selective modulators of group I metabotropic glutamate receptors as potential antiepileptic agents.
Subject(s)
Anticonvulsants/pharmacology , Non-Nutritive Sweeteners/pharmacology , Seizures/drug therapy , Taste/drug effects , AnimalsABSTRACT
A virtual screening campaign was conducted in order to discover new anticonvulsant drug candidates for the treatment of refractory epilepsy. To this purpose, a topological discriminant function to identify antiMES drugs and a sequential filtering methodology to discriminate P-glycoprotein substrates and nonsubstrates were jointly applied to ZINC 5 and DrugBank databases. The virtual filters combine an ensemble of 2D classifiers and docking simulations. In the light of the results, 10 structurally diverse compounds were acquired and tested in animal models of seizure and the rotorod test. All 10 candidates showed some level of protection against MES test.
Subject(s)
Anticonvulsants/pharmacology , Drug Evaluation, Preclinical/methods , Epilepsy/drug therapy , User-Computer Interface , ATP Binding Cassette Transporter, Subfamily B, Member 1/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Anticonvulsants/therapeutic use , Humans , Mice , Models, Molecular , Protein Conformation , Treatment FailureABSTRACT
A virtual screening campaign based on application of a topological discriminant function capable of identifying novel anticonvulsant agents indicated several widely-used artificial sweeteners as potential anticonvulsant candidates. Acesulfame potassium, cyclamate and saccharin were tested in the Maximal Electroshock Seizure model (mice, ip), showing moderate anticonvulsant activity. We hypothesized a probable structural link between the receptor responsible of sweet taste and anticonvulsant molecular targets. Bioinformatic tools confirmed a highly significant sequence-similarity between taste-related protein T1R3 and several metabotropic glutamate receptors from different species, including glutamate receptors upregulated in epileptogenesis and certain types of epilepsy.
