ABSTRACT
The novel cinnamic acid (CA) (H4-CA, H5-CA, and H7-CA) and caffeic acid (KA) (H4-KA, H5-KA, and H7-KA) hemorphin analogs have recently been synthesized and their trans isomers have been tested for antiseizure and antinociceptive activity. In the present study, the cis forms of these compounds were tested and compared with their trans isomers in seizure and nociception tests in mice. The cis-H5-CA and H7-CA compounds showed efficacy against psychomotor seizures, whereas the trans isomers were ineffective. Both the cis and trans KA isomers were ineffective in the 6-Hz test. In the maximal electroshock (MES) test, the cis isomers showed superior antiseizure activity to the trans forms of CA and KA conjugates, respectively. The suppression of seizure propagation by cis-H5-CA and the cis-H5-KA was reversed by a kappa opioid receptor (KOR) antagonist. Naloxone and naltrindole were not effective. The cis-isomers of CA conjugates and cis-H7-KA produced significantly stronger antinociceptive effects than their trans-isomers. The cis-H5-CA antinociception was blocked by naloxone in the acute phase and by naloxone and KOR antagonists in the inflammatory phase of the formalin test. The antinociception of the KA conjugates was not abolished by opioid receptor blockade. None of the tested conjugates affected the thermal nociceptive threshold. The results of the docking analysis also suggest a model-specific mechanism related to the activity of the cis-isomers of CA and KA conjugates in relation to opioid receptors. Our findings pave the way for the further development of novel opioid-related antiseizure and antinociceptive therapeutics.
Subject(s)
Analgesics , Anticonvulsants , Caffeic Acids , Cinnamates , Seizures , Animals , Analgesics/pharmacology , Analgesics/chemistry , Analgesics/chemical synthesis , Anticonvulsants/pharmacology , Anticonvulsants/chemistry , Anticonvulsants/chemical synthesis , Mice , Male , Seizures/drug therapy , Cinnamates/pharmacology , Cinnamates/chemistry , Cinnamates/chemical synthesis , Cinnamates/therapeutic use , Caffeic Acids/pharmacology , Caffeic Acids/chemistry , Caffeic Acids/therapeutic use , Caffeic Acids/chemical synthesis , Peptides/pharmacology , Peptides/chemistry , Peptides/chemical synthesis , Peptides/therapeutic use , Molecular Docking Simulation , IsomerismABSTRACT
BACKGROUND: Epilepsy poses a significant global health challenge, particularly in regions with limited financial resources hindering access to treatment. Recent research highlights neuroinflammation, particularly involving cyclooxygenase-2 (COX-2) pathways, as a promising avenue for epilepsy management. METHODS: This study aimed to develop a Cyclooxygenase-2 inhibitor with potential anticonvulsant properties. A promising drug candidate was identified and chemically linked with phospholipids through docking analyses. The activation of this prodrug was assessed using phospholipase A2 (PLA2)-mediated hydrolysis studies. The conjugate's confirmation and cytotoxicity were evaluated using Fourier Transform Infrared Spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), and Sulphoramide B (SRB) assays. RESULTS: Docking studies revealed that the Celecoxib-Phospholipid conjugate exhibited a superior affinity for PLA2 compared to other drug-phospholipid conjugates. FT-IR spectroscopy confirmed the successful synthesis of the conjugate, while DSC analysis confirmed its purity and formation. PLA2-mediated hydrolysis experiments demonstrated selective activation of the prodrug depending on PLA2 concentration. SRB experiments indicated dose-dependent cytotoxic effects of Celecoxib, phospholipid non-toxicity, and efficient celecoxib-phospholipid conjugation. CONCLUSION: This study successfully developed a Celecoxib-phospholipid conjugate with potential anticonvulsant properties. The prodrug's specific activation and cytotoxicity profile makes it a promising therapeutic candidate. Further investigation into underlying mechanisms and in vivo studies is necessary to assess its translational potential fully.
Subject(s)
Anticonvulsants , Celecoxib , Molecular Docking Simulation , Phospholipases A2 , Phospholipids , Prodrugs , Celecoxib/pharmacology , Phospholipids/chemistry , Anticonvulsants/pharmacology , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Prodrugs/pharmacology , Prodrugs/chemistry , Prodrugs/chemical synthesis , Phospholipases A2/metabolism , Humans , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/chemical synthesis , Spectroscopy, Fourier Transform Infrared/methods , Animals , Calorimetry, Differential Scanning , Epilepsy/drug therapy , Hydrolysis , Cell Survival/drug effectsABSTRACT
Dysfunction of voltage-gated sodium channel Nav1.2 causes various epileptic disorders, and inhibition of the channel has emerged as an attractive therapeutic strategy. However, currently available Nav1.2 inhibitors exhibit low potency and limited structural diversity. In this study, a novel series of pyrimidine-based derivatives with Nav1.2 inhibitory activity were designed, synthesized, and evaluated. Compounds 14 and 35 exhibited potent activity against Nav1.2, boasting IC50 values of 120 and 65 nM, respectively. Compound 14 displayed favorable pharmacokinetics (F = 43%) following intraperitoneal injection and excellent brain penetration potency (B/P = 3.6). Compounds 14 and 35 exhibited robust antiepileptic activities in the maximal electroshock test, with ED50 values of 3.2 and 11.1 mg/kg, respectively. Compound 35 also demonstrated potent antiepileptic activity in a 6 Hz (32 mA) model, with an ED50 value of 18.5 mg/kg. Overall, compounds 14 and 35 are promising leads for the development of new small-molecule therapeutics for epilepsy.
Subject(s)
Anticonvulsants , Epilepsy , NAV1.2 Voltage-Gated Sodium Channel , Pyrimidines , Animals , Pyrimidines/pharmacology , Pyrimidines/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Pyrimidines/therapeutic use , Anticonvulsants/pharmacology , Anticonvulsants/chemistry , Anticonvulsants/chemical synthesis , Anticonvulsants/therapeutic use , Anticonvulsants/pharmacokinetics , Epilepsy/drug therapy , Epilepsy/metabolism , Mice , NAV1.2 Voltage-Gated Sodium Channel/metabolism , Structure-Activity Relationship , Humans , Disease Models, Animal , Male , Voltage-Gated Sodium Channel Blockers/pharmacology , Voltage-Gated Sodium Channel Blockers/chemistry , Voltage-Gated Sodium Channel Blockers/chemical synthesis , Voltage-Gated Sodium Channel Blockers/pharmacokinetics , Voltage-Gated Sodium Channel Blockers/therapeutic use , Drug Discovery , Electroshock , Molecular Docking SimulationABSTRACT
Owing to their incomplete digestion in the human body and inadequate removal by sewage treatment plants, antiepileptic drugs (AEDs) accumulate in water bodies, potentially affecting the exposed humans and aquatic organisms. Therefore, sensitive and reliable detection methods must be urgently developed for monitoring trace AEDs in environmental water samples. Herein, a novel phenylboronic acid-functionalized magnetic cyclodextrin microporous organic network (Fe3O4@CD-MON-PBA) was designed and synthesized via the thiol-yne click post-modification strategy for selective and efficient magnetic solid-phase extraction (MSPE) of trace AEDs from complex sample matrices through the specific B-N coordination, π-π, hydrogen bonding, electrostatic, and host-guest interactions. Fe3O4@CD-MON-PBA exhibited a large surface area (118.5 m2 g-1), rapid magnetic responsiveness (38.6 emu g-1, 15 s), good stability and reusability (at least 8 times), and abundant binding sites for AEDs. Under optimal extraction conditions, the proposed Fe3O4@CD-MON-PBA-MSPE-HPLC-UV method exhibited a wide linear range (0.5-1000 µg L-1), low limits of detection (0.1-0.5 µg L-1) and quantitation (0.3-2 µg L-1), good anti-interference ability, and large enrichment factors (92.2-104.3 to 92.3-98.0) for four typical AEDs. This work confirmed the feasibility of the thiol-yne click post-synthesis strategy for constructing novel and efficient multifunctional magnetic CD-MONs for sample pretreatment and elucidated the significance of B-N coordination between PBA and N-containing AEDs.
Subject(s)
Anticonvulsants , Boronic Acids , Click Chemistry , Cyclodextrins , Solid Phase Extraction , Sulfhydryl Compounds , Boronic Acids/chemistry , Anticonvulsants/chemistry , Anticonvulsants/isolation & purification , Anticonvulsants/chemical synthesis , Solid Phase Extraction/methods , Cyclodextrins/chemistry , Porosity , Sulfhydryl Compounds/chemistry , Alkynes/chemistry , Water Pollutants, Chemical/chemistry , Water Pollutants, Chemical/analysis , Water Pollutants, Chemical/isolation & purification , Limit of DetectionABSTRACT
In the present study, a series of original alaninamide derivatives have been designed applying a combinatorial chemistry approach, synthesized, and characterized in the in vivo and in vitro assays. The obtained molecules showed potent and broad-spectrum activity in basic seizure models, namely, the maximal electroshock (MES) test, the 6 Hz (32 mA) seizure model, and notably, the 6 Hz (44 mA) model of pharmacoresistant seizures. Most potent compounds 26 and 28 displayed the following pharmacological values: ED50 = 64.3 mg/kg (MES), ED50 = 15.6 mg/kg (6 Hz, 32 mA), ED50 = 29.9 mg/kg (6 Hz, 44 mA), and ED50 = 34.9 mg/kg (MES), ED50 = 12.1 mg/kg (6 Hz, 32 mA), ED50 = 29.5 mg/kg (6 Hz, 44 mA), respectively. Additionally, 26 and 28 were effective in the ivPTZ seizure threshold test and had no influence on the grip strength. Moreover, lead compound 28 was tested in the PTZ-induced kindling model, and then, its influence on glutamate and GABA levels in the hippocampus and cortex was evaluated by the high-performance liquid chromatography (HPLC) method. In addition, 28 revealed potent efficacy in formalin-induced tonic pain, capsaicin-induced pain, and oxaliplatin- and streptozotocin-induced peripheral neuropathy. Pharmacokinetic studies and in vitro ADME-Tox data proved favorable drug-like properties of 28. The patch-clamp recordings in rat cortical neurons showed that 28 at a concentration of 10 µM significantly inhibited fast sodium currents. Therefore, 28 seems to be an interesting candidate for future preclinical development in epilepsy and pain indications.
Subject(s)
Analgesics , Anticonvulsants , Seizures , Animals , Anticonvulsants/pharmacology , Anticonvulsants/chemistry , Anticonvulsants/chemical synthesis , Analgesics/pharmacology , Seizures/drug therapy , Male , Rats , Mice , Disease Models, Animal , Rats, Wistar , Hippocampus/drug effects , Hippocampus/metabolism , Electroshock , Neurons/drug effects , Neurons/metabolismABSTRACT
Two series, "a" and "b", each consisting of nine chemical compounds, with 2,3-disubstituted quinazolin-4(3H)-one scaffold, were synthesized and evaluated for their anticonvulsant activity. They were investigated as dual potential positive allosteric modulators of the GABAA receptor at the benzodiazepine binding site and inhibitors of carbonic anhydrase II. Quinazolin-4(3H)-one derivatives were evaluated in vivo (D1-3 = 50, 100, 150 mg/kg, administered intraperitoneally) using the pentylenetetrazole (PTZ)-induced seizure model in mice, with phenobarbital and diazepam, as reference anticonvulsant agents. The in silico studies suggested the compounds act as anticonvulsants by binding on the allosteric site of GABAA receptor and not by inhibiting the carbonic anhydrase II, because the ligands-carbonic anhydrase II predicted complexes were unstable in the molecular dynamics simulations. The mechanism targeting GABAA receptor was confirmed through the in vivo flumazenil antagonism assay. The pentylenetetrazole experimental anticonvulsant model indicated that the tested compounds, 1a-9a and 1b-9b, present a potential anticonvulsant activity. The evaluation, considering the percentage of protection against PTZ, latency until the onset of the first seizure, and reduction in the number of seizures, revealed more favorable results for the "b" series, particularly for compound 8b.
Subject(s)
Anticonvulsants , Pentylenetetrazole , Receptors, GABA-A , Seizures , Anticonvulsants/pharmacology , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Animals , Mice , Seizures/drug therapy , Seizures/chemically induced , Receptors, GABA-A/metabolism , Quinazolinones/pharmacology , Quinazolinones/chemistry , Quinazolinones/chemical synthesis , Molecular Docking Simulation , Male , Structure-Activity Relationship , Molecular Dynamics Simulation , Computer Simulation , Disease Models, Animal , Molecular Structure , Allosteric SiteABSTRACT
The therapeutic use of the traditional drugs against epilepsy has been hindered by their toxicity and low selectivity. These limitations have stimulated the design and development of new generations of antiepileptic drugs. This review explores the molecular targets and synthesis of the antiepileptic drugs that have entered the market in the 21st century, with a focus on manufacturer synthesis.
Subject(s)
Anticonvulsants , Epilepsy , Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Anticonvulsants/chemistry , Anticonvulsants/therapeutic use , Humans , Epilepsy/drug therapy , Animals , Molecular StructureABSTRACT
BACKGROUND: Pyridine and its derivatives play a vital role in medicinal chemistry, serving as key scaffolds for drugs. The ability to bind to biological targets makes pyridine compounds significant, sparking interest in creating new pyridine-based drugs. Thus, the purpose of the research is to synthesize new thioalkyl derivatives of pyridine, predict their biological spectrum, study their psychotropic properties, and based on these findings, perform structure-activity relationships to assess pharmacophore functional groups. METHODS: Classical organic methods were employed for synthesizing new thioalkyl derivatives of pyridine, with a multifaceted pharmacological profiles. Various software packages and methods were employed to evaluate the biological spectrum of the newly synthesized compounds. For the evaluation of neurotropic activity of new synthesized compounds, some biological methods were used according to indicators characterizing anticonvulsant, sedative and antianxiety activity as well as side effects. RESULTS: Effective synthetic methods for 6-amino-4-phenyl-2-thio-2H-thiopyran-5-carboxylic acid ethyl ester, 2-amino substituted thiopyridine derivatives and 6-cycloamino-2-thioalkyl-4-phenylnicotinate derivatives were obtained in high yield. Predicted biological spectra and pharmacokinetic data indicated high gastrointestinal absorption and low blood-brain barrier passage for most compounds and demonstrated potential various biological effects, particularly psychotropic properties. Studied compounds demonstrated high anticonvulsant activity through antagonism with pentylenetetrazole. They exhibited low toxicity without inducing muscle relaxation in the studied doses. In psychotropic studies, the compounds displayed activating, sedative, and anxiolytic effects. Notably, the 6-amino-2-thioalkyl-4-phenylnicotinate derivatives demonstrated significant anxiolytic activity (about four times more compared to diazepam). They also exhibited pronounced sedative effects. Ethyl 2-({2-[(diphenylmethyl)amino]-2-oxoethyl}thio)-4-phenyl-6-pyrrolidin-1-ylnicotinate exhibited anxiolytic activity even two times greater than diazepam. Moreover, all studied compounds showed statistically significant antidepressant effects. Noteworthy ethyl 2-({2-oxo-2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}thio)-4-phenyl-6-pyrrolidin-1-ylnicotinate showcasing its unique psychotropic effect. CONCLUSIONS: The selected compounds demonstrate anticonvulsant properties, activating behavior, and anxiolytic effects, while simultaneously exhibiting antidepressant effects and these compounds as promising candidates for further exploration in the development of therapeutics with a broad spectrum of neuropsychiatric applications.
Subject(s)
Anti-Anxiety Agents , Anticonvulsants , Pyridines , Structure-Activity Relationship , Pyridines/chemistry , Pyridines/pharmacology , Pyridines/chemical synthesis , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Anticonvulsants/chemistry , Mice , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/chemistry , Molecular Structure , Dose-Response Relationship, Drug , Male , Seizures/drug therapy , Hypnotics and Sedatives/pharmacology , Hypnotics and Sedatives/chemical synthesis , Hypnotics and Sedatives/chemistry , PentylenetetrazoleABSTRACT
Tetrahydrolinalool (THL) is an acyclic monoterpene alcohol, produced during linalol metabolism and also a constituent of essential oils. As described in the literature, many monoterpenes present anticonvulsant properties, and thus we became interested in evaluating the anticonvulsant activity of Tetrahydrolinalool using in mice model as well as in silico approaches. Our results demonstrated that THL increased latency to seizure onset and also reduced the mortality, in picrotoxin induced seizure tests. The results may be related to GABAergic regulation, which was also suggested in seizure testing induced by 3-mercapto-propionic acid. In the strychnine-induced seizure testing, none of the groups pretreated with THL modulated the parameters indicative of anticonvulsant effect. The electrophysiological results revealed that THL treatment reduces seizures induced by pentylenetetrazole. The in silico molecular docking studies showed that the interaction between THL and a GABAA receptor model formed a stable complex, in comparison to the crystaligraphic structure of diazepam, a structurally related ligand. In conclusion, all the evidences showed that THL presents effective anticonvulsant activity related to the GABAergic pathway, being a candidate for treatment of epileptic syndromes.
Subject(s)
Acyclic Monoterpenes , Anticonvulsants , Molecular Docking Simulation , Monoterpenes , Pentylenetetrazole , Seizures , Anticonvulsants/pharmacology , Anticonvulsants/chemistry , Anticonvulsants/chemical synthesis , Animals , Mice , Seizures/drug therapy , Monoterpenes/pharmacology , Monoterpenes/chemistry , Monoterpenes/chemical synthesis , Acyclic Monoterpenes/pharmacology , Acyclic Monoterpenes/chemistry , Acyclic Monoterpenes/chemical synthesis , Male , Receptors, GABA-A/metabolism , Receptors, GABA-A/chemistry , Structure-Activity Relationship , Behavior, Animal/drug effects , Picrotoxin/pharmacologyABSTRACT
Some new hemorphin-4 analogs with structures of Xxx-Pro-Trp-Thr-NH2 and Tyr-Yyy-Trp-Thr-NH2, where Xxx is 2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoic acid or 2-amino-3-(4-dibenzylamino-2,6-dimethylphenyl)propanoic acid, and Yyy is (2S,4S)-4-amino-pyrrolidine-2-carboxylic acid, were synthesized and characterized by electrochemical and spectral analyses. In vivo anticonvulsant and antinociceptive activities of peptide derivatives were studied after intracerebroventricular injection in mice. The therapeutic effects of the modified peptides on seizures and pain in mice were evaluated to provide valuable insights into the potential applications of the novel compounds. Electrochemical characterization showed that the compounds behave as weak protolytes and that they are in a soluble, stable molecular form at physiological pH values. The antioxidant activity of the peptides was evaluated with voltammetric analyses, which were confirmed by applying the 2,2-Diphenyl-1-picrylhydrazyl method. The compounds showed satisfactory results regarding their structural stability, reaching the desired centers for the manifestation of biological activity without hydrolysis processes at 37°C and physiological pH. Dm-H4 and H4-P1 exhibited 100% and 83% potency to suppress the psychomotor seizures in the 6-Hz test compared to 67% activity of H4. Notably, only the H4-P1 had efficacy in blocking the tonic component in the maximal electroshock test with a potency comparable to H4. All investigated peptides containing unnatural conformationally restricted amino acids showed antinociceptive effects. The analogs Db-H4 and H4-P1 showed the most pronounced and long-lasting effect in both experimental models of pain induced by thermal and chemical stimuli. Dm-H4 produced a dose-dependent thermal antinociception and H4-P2 inhibited only formalin-induced pain behavior.
Subject(s)
Seizures , Animals , Mice , Male , Seizures/drug therapy , Structure-Activity Relationship , Anticonvulsants/pharmacology , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Pain/drug therapy , Amino Acids/chemistry , Amino Acids/pharmacology , Amino Acids/chemical synthesis , Antioxidants/pharmacology , Antioxidants/chemical synthesis , Antioxidants/chemistry , Analgesics/pharmacology , Analgesics/chemical synthesis , Analgesics/chemistry , Dose-Response Relationship, Drug , Disease Models, Animal , Opioid Peptides/pharmacology , Opioid Peptides/chemical synthesis , Opioid Peptides/chemistry , Analgesics, Opioid/pharmacology , Analgesics, Opioid/chemical synthesis , Analgesics, Opioid/chemistryABSTRACT
N-Arylenaminones are highly versatile compounds which can be synthesized in relatively simple ways. In this work we explored the synthesis of the four monosubstituted N-(4-R-phenyl)enaminones 3 a (R=NO2), 3 b (R=F), 3 c (R=H), and 3 d (R=OMe) with the goal of determining the influence of the substituents' electronic effects on tautomer stability and biological activity. These compounds were analyzed by means of Density Functional Theory calculations (DFT), to evaluate the relative stability of the possible tautomers. We found that the enaminone structure is the most stable with respect to the ketoimine and iminoenol forms. In addition, all four compounds display anticonvulsant activity, with 3 d being the one that mostly increased latency and mostly decreased the number of convulsions with respect to the control group. The suggested mechanism of action involves blockage of the voltage-dependent Na+ channels, considering that these molecules meet the structural characteristics needed to block the receptor, as is the case of the positive control molecules phenytoin (PHT) and valproic acid (VPA).
Subject(s)
Anticonvulsants , Density Functional Theory , Anticonvulsants/pharmacology , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Animals , Seizures/drug therapy , Structure-Activity Relationship , Mice , Molecular StructureABSTRACT
Trying to meet the multitarget-directed ligands strategy, a series of previously described aryl-substituted phenylalanine derivatives, reported as competitive antagonists of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, were screened in vitro for their free-radical scavenging and antioxidant capacity in two different assays: ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity fluorescent (ORAC-FL) assays. The most active antioxidants 1 and 8 were further examined to evaluate their neuroprotective properties in vitro. In this study, compound 1 showed a significant neuroprotective effect against the neurotoxin 6-hydroxydopamine in neuroblastoma SH-SY5Y and IMR-32 cell lines. Both compounds also showed prevention from high levels of reactive oxygen species (ROS) in SH-SY5Y cells. Furthermore, the desired monoamine oxidase B (MAO-B) inhibition effect (IC50 = 278 ± 29 nM) for 1 was determined. No toxic effects up to 100 µM of 1 and 8 against neuroblastoma cells were observed. Furthermore, in vivo studies showed that compound 1 demonstrated significant anticonvulsant potential in 6-Hz test, but in neuropathic pain models its antiallodynic and antihyperalgesic properties were not observed. Concluding, the compound 1 seems to be of higher importance as a new phenylalanine-based lead candidate due to its confirmed promise in in vitro and in vivo anticonvulsant activity.
Subject(s)
Anticonvulsants , Monoamine Oxidase Inhibitors , Monoamine Oxidase/metabolism , Neuroprotective Agents , Phenylalanine , Receptors, AMPA/antagonists & inhibitors , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Cell Line, Tumor , Humans , Male , Mice , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Oxidopamine/toxicity , Phenylalanine/analogs & derivatives , Phenylalanine/chemical synthesis , Phenylalanine/chemistry , Phenylalanine/pharmacology , Receptors, AMPA/metabolismABSTRACT
A series of 7-alkoxy - [1,2,4] triazolo [1, 5-a] pyrimidine derivatives were designed and synthesized. Maximal electroshock (MES) and pentylenetetrazole (PTZ) tests were utilized to access their anticonvulsant activity. Most of the series of compounds exhibited significant anti-seizure effects. Further studies demonstrated that the anticonvulsant activity of these compounds mainly depended on their allosteric potentiation of GABAA receptors. Among them, compound 10c was picked for the mechanism study due to its potent activity. The compound is more sensitive to subunit configurations of synaptic α1ß2γ2 and extrasynaptic α4ß3δ GABAA receptors, but there were no effects on NMDA receptors and Nav1.2 sodium channels. Meanwhile, 10c acted on the sites of GABAA receptors distinct from commonly used anticonvulsants benzodiazepines and barbiturates. Furthermore, studies from native neurons demonstrated that compound 10c also potentiated the activity of native GABAA receptors and reduced action potential firings in cultured cortical neurons. Such structural compounds may lay a foundation for further designing novel antiepileptic molecules.
Subject(s)
Anticonvulsants/pharmacology , Epilepsy/drug therapy , Pyrimidines/pharmacology , Receptors, GABA-A/metabolism , Seizures/drug therapy , Triazoles/pharmacology , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Cells, Cultured , Dose-Response Relationship, Drug , Drug Discovery , Electroshock , Epilepsy/chemically induced , Epilepsy/metabolism , Male , Mice , Mice, Inbred Strains , Molecular Structure , Neurons/drug effects , Neurons/metabolism , Pentylenetetrazole , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Rats, Sprague-Dawley , Seizures/chemically induced , Seizures/metabolism , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
Epilepsy is a disease that affects millions of people around the globe and has a multifactorial cause. Inflammation is a process that can be involved in the development of seizures. Thus, the present study proposed the design and synthesis of new candidates for antiepileptic drugs that would also control the inflammatory process. Nine new derivatives of the substituted thiazophthalimide hybrid core were obtained with satisfactory purity ≥99% and yields between 27% and 87%. All compounds showed cell viability values greater than 90% in the culture of PBMC cells from healthy volunteers and, therefore, were not considered cytotoxic. These compounds modulated proinflammatory cytokines IFN-y and IL-17A and can mitigate inflammation. Acute toxicity studies of compound 7i in an animal model indicated that the compound has low toxicity and an LD50 greater than 2 g/kg in healthy adult rats. The same compound did not show positive results for anticonvulsant activity through the PTZ test. However, 7i demonstrates the interaction with the target GABA-A receptor in silico, indicating a possible activity as an agonist of that receptor. Thus, further studies are needed to investigate the anticonvulsant activity, in particular, using models in which the inflammatory process triggers epileptic seizures.
Subject(s)
Anticonvulsants/therapeutic use , Epilepsy/drug therapy , Phthalimides/therapeutic use , Seizures/drug therapy , Thiazoles/therapeutic use , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Cells, Cultured , Dose-Response Relationship, Drug , Epilepsy/pathology , Humans , Male , Molecular Docking Simulation , Molecular Structure , Phthalimides/chemical synthesis , Phthalimides/chemistry , Rats , Rats, Wistar , Seizures/pathology , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
The discovery of novel analgesic agents with high potency, low toxicity and low addictive properties remain a priority. This study aims to identify the analgesic potential of quinoline derived α-trifluoromethylated alcohols (QTA) and their mechanism of action. We synthesized and characterized several compounds of QTAs and screened them for antiepileptic and analgesic activity using zebrafish larvae in high thorough-put behavior analyses system. Toxicity and behavioral screening of 9 compounds (C1-C9) identified four candidates (C2, C3, C7 and C9) with antiepileptic properties that induces specific and reversible reduction in photomotor activity. Importantly, compounds C2 and C3 relieved the thermal pain response in zebrafish larvae indicating analgesic property. Further, using novel inâ vivo CoroNa green assay, we show that compounds C2 and C3 block sodium channels and reduce inflammatory sodium signals released by peripheral nerve and tissue damage. Thus, we have identified novel QTA compounds with antiepileptic and analgesic properties which could alleviate neuropathic pain.
Subject(s)
Analgesics/pharmacology , Anticonvulsants/pharmacology , Methanol/analogs & derivatives , Quinolines/pharmacology , Sodium Channel Blockers/pharmacology , Sodium Channels/metabolism , Analgesics/chemical synthesis , Analgesics/chemistry , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Dose-Response Relationship, Drug , Drug Discovery , Methanol/chemical synthesis , Methanol/chemistry , Methanol/pharmacology , Molecular Structure , Quinolines/chemical synthesis , Quinolines/chemistry , Sodium Channel Blockers/chemical synthesis , Sodium Channel Blockers/chemistry , Structure-Activity Relationship , ZebrafishABSTRACT
Based on the biological importance of the thiazole nucleus, we decided to prepare and evaluate the biological activity of some new isatin derivatives containing thiazole moiety. The 5-(piperidin-1-ylsulfonyl)indoline-2,3-dione (1) was prepared and used as a starting material in the synthesis of many isatin derivatives for anticonvulsant evaluation. All the newly synthesized thiazlidino/thiosemicarbazide-indolin-2-one derivatives screened in vivo for their anticonvulsant activity against pentylenetetrazole-induced convulsions in mice. The results were compared with phenobarbitone sodium as a standard anticonvulsant drug. Most of the tested compounds exhibited anticonvulsant activity with relative potency ranging from 0.02 to 0.2 in comparison to standard drug phenobarbitone. The most active compounds 3, 6a, 6c and 8, were exposed to further investigations in rats to evaluate the effect of most active derivatives on the haematological, liver, kidney functions as well as histopathological studies of the liver and kidney tissues. Finally, the most potent compounds 3, 6a, 6c and 8 observed good toxic properties for both liver and kidney function with mild variability changes on RBCs, WBCs, Platelets, Hb, AST, ALT, and creatinine level, as well as kidney and liver tissue and these good results obtained rather than used low dose from phenobarbitone.
Subject(s)
Anticonvulsants/pharmacology , Seizures/drug therapy , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Injections, Intraperitoneal , Male , Mice , Molecular Structure , Oxindoles/chemistry , Oxindoles/pharmacology , Pentylenetetrazole/administration & dosage , Piperidines/chemistry , Piperidines/pharmacology , Seizures/chemically induced , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacology , Thiosemicarbazones/chemistry , Thiosemicarbazones/pharmacologyABSTRACT
BACKGROUND: Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to the Cl-ionophore. Benzodiazepines enhance GABA-ergic transmission and this has led to a study of the role of GABA in anxiety. The search for anxiolytics and anticonvulsive agents has involved glutamate-ergic, 5HT-ergic substances and neuropeptides. However, each of these well-known anxiolytics, anticonvulsants and cognition enhancers (nootropics) has repeatedly been reported to have many adverse side effects, therefore there is an urgent need to search for new drugs able to restore damaged cognitive functions without causing significant adverse reactions. OBJECTIVE: Considering the relevance of epilepsy diffusion in the world, we have addressed our attention to the discovery of new drugs in this field Thus our aim is the synthesis and study of new compounds with antiepileptic (anticonvulsant) and not only, activity. METHODS: For the synthesis of compounds classical organic methods were used and developed. For the evaluation of biological activity some anticonvulsant and psychotropic methods were used. RESULTS: As a result of multistep reactions 26 new, five-membered heterocyclic systems were obtained. PASS prediction of anticonvulsant activity was performed for the whole set of the designed molecules and probability to be active Pa values were ranging from 0.275 to 0.43. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures, anti-thiosemicarbazides effect as well as some psychotropic effect. The biological assays evidenced that some of the studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of compounds is low and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity it was found that the selected compounds have an activating behavior and anxiolytic effects on the models of "open field" and "elevated plus maze" (EPM). The data obtained indicate the anxiolytic (anti-anxiety) activity of the derivatives of pyrimidines, especially pronounced in compounds 6n, 6b, and 7c. The studied compounds increase the latent time of first immobilization on the model of "forced swimming" (FST) and exhibit some antidepressant effect similarly to diazepam. Docking studies revealed that compound 6k bound tightly in the active site of GABAA receptor with a value of the scoring function that estimates free energy of binding (ΔG) at -7.95 kcal/mol, while compound 6n showed the best docking score and seems to be dual inhibitor of SERT transporter as well as 5-HT1A receptor. CONCLUSIONS: Тhe selected compounds have an anticonvulsant, activating behavior and anxiolytic effects, at the same time exhibit some antidepressant effect.
Subject(s)
Azepines/administration & dosage , Azepines/chemical synthesis , Pyrimidines/administration & dosage , Pyrimidines/chemical synthesis , Seizures/drug therapy , Animals , Anti-Anxiety Agents/administration & dosage , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Anticonvulsants/administration & dosage , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Azepines/chemistry , Azepines/pharmacology , Disease Models, Animal , Male , Maze Learning/drug effects , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Pentylenetetrazole/adverse effects , Pyrimidines/chemistry , Pyrimidines/pharmacology , RNA-Binding Proteins/chemistry , RNA-Binding Proteins/metabolism , Rats , Receptors, GABA-A/chemistry , Receptors, GABA-A/metabolism , Seizures/chemically induced , Seizures/physiopathologyABSTRACT
Epilepsy affects around 50 million people worldwide, and an important number of patients (30%) fail to respond to any available antiepileptic drug. Previous studies have shown that luteolin presents a promising potential as an anticonvulsant. On the other hand, different studies showed that luteolin does not promote anticonvulsant effects. Therefore, there is a lack of consensus about the use of luteolin for seizure control. Luteolin low bioavailability could be a limiting factor to obtain better results. Attractively, micronization technology has been applied to improve flavonoids bioavailability. Thus, the present study aimed to investigate the effects of luteolin on its raw form and micronized luteolin in a PTZ-induced seizure model in adult zebrafish (Danio rerio). Our results demonstrate that luteolin and micronized luteolin did not block PTZ-induced seizures in adult zebrafish. Also, luteolin and micronized luteolin did not provoke behavioral changes. Finally, our results show that 24 h after seizure occurrence, no changes were detected for p70S6Kb, interleukin 1ß, and caspase-3 transcript levels. Altogether, we failed to observe an anticonvulsant potential of luteolin in adult zebrafish, even in its micronized form. However, we recommend new studies to investigate luteolin benefits in epilepsy.
Subject(s)
Anticonvulsants/administration & dosage , Anticonvulsants/chemical synthesis , Luteolin/administration & dosage , Luteolin/chemical synthesis , Seizures/drug therapy , Age Factors , Animals , Dose-Response Relationship, Drug , Female , Male , Particle Size , Pentylenetetrazole/toxicity , Seizures/chemically induced , ZebrafishABSTRACT
In the present study, we compared the antiepileptic effects of α-asarone derivatives to explore their structure-activity relationships using the PTZ-induced seizure model. Our research revealed that electron-donating methoxy groups in the 3,4,5-position on phenyl ring increased antiepileptic potency but the placement of other groups at different positions decreased activity. Besides, in allyl moiety, the optimal activity was reached with either an allyl or a 1-butenyl group in conjugation with the benzene ring. The compounds 5 and 19 exerted better neuroprotective effects against epilepsy in vitro (cell) and in vivo (mouse) models. This study provides valuable data for further exploration and application of these compounds as potential anti-seizure medicines.
Subject(s)
Allylbenzene Derivatives/chemistry , Allylbenzene Derivatives/therapeutic use , Anisoles/chemistry , Anisoles/therapeutic use , Anticonvulsants/chemistry , Anticonvulsants/therapeutic use , Epilepsy/drug therapy , Allylbenzene Derivatives/chemical synthesis , Animals , Anisoles/chemical synthesis , Anticonvulsants/chemical synthesis , Cells, Cultured , Disease Models, Animal , Male , Mice , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Neuroprotective Agents/therapeutic use , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
γ-Aminobutyric acid (GABA) neurotransmission has a significant impact on the proper functioning of the central nervous system. Numerous studies have indicated that inhibitors of the GABA transporters mGAT1-4 offer a promising strategy for the treatment of several neurological disorders, including epilepsy, neuropathic pain, and depression. Following our previous results, herein, we report the synthesis, biological evaluation, and structure-activity relationship studies supported by molecular docking and molecular dynamics of a new series of N-benzyl-4-hydroxybutanamide derivatives regarding their inhibitory potency toward mGAT1-4. This study allowed us to identify compound 23a (N-benzyl-4-hydroxybutanamide bearing a dibenzocycloheptatriene moiety), a nonselective GAT inhibitor with a slight preference toward mGAT4 (pIC50 = 5.02 ± 0.11), and compound 24e (4-hydroxy-N-[(4-methylphenyl)-methyl]butanamide bearing a dibenzocycloheptadiene moiety) with relatively high inhibitory activity toward mGAT2 (pIC50 = 5.34 ± 0.09). In a set of in vivo experiments, compound 24e successively showed predominant anticonvulsant activity and antinociception in the formalin model of tonic pain. In contrast, compound 23a showed significant antidepressant-like properties in mice. These results were consistent with the available literature data, which indicates that, apart from seizure control, GABAergic neurotransmission is also involved in the pathophysiology of several psychiatric diseases, however alternative mechanisms underlying this action cannot be excluded. Finally, it is worth noting that the selected compounds showed unimpaired locomotor skills that have been indicated to give reliable results in behavioral assays.