RESUMO
Human ß3-adrenoceptor (ß3AR) agonists were considered potential agents for the treatment of metabolic disorders. However, compounds tested as ß3AR ligands have shown marked differences in pharmacological profile in rodent and human species, although these compounds remain attractive as they were successfully repurposed for the therapy of urinary incontinence. In this work, some biarylamine compounds were designed and tested in silico as potential ß3AR agonists on 3-D models of mouse or human ß3ARs. Based on the theoretical results, we identified, synthesized and tested a biarylamine compound (polibegron). In CHO-K1 cells expressing the human ß3AR, polibegron and the ß3AR agonist BRL 37344 were partial agonists for stimulating cAMP accumulation (50 and 57% of the response to isoproterenol, respectively). The potency of polibegron was 1.71- and 4.5-fold higher than that of isoproterenol and BRL37344, respectively. These results indicate that polibegron acts as a potent, but partial, agonist at human ß3ARs. In C57BL/6N mice with obesity induced by a high-fat diet, similar effects of the equimolar intraperitoneal administration of polibegron and BRL37344 were observed on weight, visceral fat and plasma levels of glucose, cholesterol and triglycerides. Similarities and differences between species related to ligand-receptor interactions can be useful for drug designing.
Assuntos
Agonistas Adrenérgicos beta , Receptores Adrenérgicos beta 3 , Cricetinae , Humanos , Camundongos , Animais , Isoproterenol , Receptores Adrenérgicos beta 3/metabolismo , Camundongos Endogâmicos C57BL , Células CHO , Cricetulus , Agonistas Adrenérgicos beta/farmacologiaRESUMO
The GABAergic and glutamatergic neurotransmission systems are involved in seizures and other disorders of the central nervous system (CNS). Benzofuran derivatives often serve as the core in drugs used to treat such neurological disorders. The aim of this study was to synthesize new γ-amino acids structurally related to GABA and derived from 2,3-disubstituted benzofurans, analyze in silico their potential toxicity, ADME properties, and affinity for the GluN1-GluN2A NMDA receptor, and evaluate their potential activity and neuronal mechanisms in a murine model of pentylenetetrazol (PTZ)- and 4-aminopyridine (4-AP)-induced seizures. The in silico analysis evidenced a low risk of toxicity for the test compounds as well as the probability that they can cross the blood-brain barrier (BBB) to reach their targets in the CNS. According to docking simulations, these compounds bind at the active site of the NMDA glutamate receptor with high affinity. The in vivo assays demonstrated that 4 protects against 4-AP-induced seizure episodes, suggesting negative allosteric modulation (NAMs) at the glutamatergic NMDA receptor. Contrarily, 3 (the regioisomer of 4) and its racemic derivatives (cis-2,3-dihydrobenzofurans) were previously described to exacerbate such episodes, pointing to their positive allosteric modulation (PAMs) of the same receptor.
Assuntos
Benzofuranos , Receptores de N-Metil-D-Aspartato , Aminoácidos , Animais , Benzofuranos/farmacologia , Ligantes , Camundongos , Pentilenotetrazol , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
BACKGROUDS: Cannabinoid receptor antagonists have been suggested as a novel treatment for obesity and diabetes. We have developed a synthetic cannabinoid receptor antagonist denominated BAR-1. As the function and integrity of a ß-cell cellular structure are important keys for diabetes onset, we evaluated the effects of pharmacological administration of BAR-1 on prediabetic and diabetic rodents. METHODS: CD-1 mice fed a hypercaloric diet or treated with streptozotocin were treated with 10 mg/kg BAR-1 for 2, 4 or 8 weeks. Body weight, oral glucose tolerance test, HbA1c, triglycerides and insulin in serum were measured. In isolated islets, we evaluated stimulated secretion and mRNA expression, and relative area of islets in fixed pancreases. Docking analysis of BAR-1 was complemented. RESULTS: BAR-1 treatment slowed down weight gain in prediabetic mice. Fasting glucose-insulin relation also decreased in BAR-1-treated mice and glucose-stimulated insulin secretion was increased in isolated islets, without effects in oral test. Diabetic mice treated with BAR-1 showed a reduced glucose and a partial recovery of islet integrity. Gene expression of insulin and glucagon showed biphasic behaviour, increasing after 4 weeks of BAR-1 administration; however, after 8 weeks, mRNA abundance decreased significantly. Administration of BAR-1 also prevents changes in endocannabinoid element expression observed in prediabetic mice. No changes were detected in other parameters studied, including the histological structure. A preliminary in-silico study suggests a close interaction with CB1 receptor. CONCLUSIONS: BAR-1 induces improvement of islet function, isolated from both prediabetic and diabetic mice. Effects of BAR-1 suggest a possible interaction with other cannabinoid receptors.
Assuntos
Antagonistas de Receptores de Canabinoides/farmacologia , Diabetes Mellitus Experimental/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Estado Pré-Diabético/metabolismo , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Teste de Tolerância a Glucose , Hemoglobinas Glicadas/análise , Insulina/sangue , Secreção de Insulina/efeitos dos fármacos , Masculino , Camundongos , Estado Pré-Diabético/tratamento farmacológico , Estado Pré-Diabético/patologia , Receptor CB1 de Canabinoide/administração & dosagem , Estreptozocina , Triglicerídeos/sangueRESUMO
Alzheimer's disease (AD) is clearly linked to the decline of acetylcholine (ACh) effects in the brain. These effects are regulated by the hydrolytic action of acetylcholinesterase (AChE). Therefore, a central palliative treatment of AD is the administration of AChE inhibitors although additional mechanisms are currently described and tested for generating advantageous therapeutic strategies. In this work, we tested new arylamides and arylimides as potential inhibitors of AChE using in silico tools. Then, these compounds were tested in vitro, and two selected compounds, C7 and C8, as well as propranolol showed inhibition of AChE. In addition, they demonstrated an advantageous acute toxicity profile compared to that of galantamine as a reference AChE inhibitor. in vivo evaluation of memory performance enhancement was performed in an animal model of cognitive disturbance with each of these compounds and propranolol individually as well as each compound combined with propranolol. Memory improvement was observed in each case, but without a significant additive effect with the combinations.
Assuntos
Amidas/administração & dosagem , Inibidores da Colinesterase/administração & dosagem , Imidas/administração & dosagem , Transtornos da Memória/tratamento farmacológico , Amidas/síntese química , Amidas/química , Amidas/uso terapêutico , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/uso terapêutico , Simulação por Computador , Modelos Animais de Doenças , Quimioterapia Combinada , Humanos , Imidas/síntese química , Imidas/química , Imidas/uso terapêutico , Masculino , Conformação Molecular , Simulação de Acoplamento Molecular , Propranolol , RatosRESUMO
Two 2,3-disubstituted benzofurans (1 and 2), analogs of gamma-aminobutyric acid (GABA), were synthesized to obtain their 2,3-dihydro derivatives from the Pd/C-driven catalytic reduction of the double bond in the furanoid ring. The synthesis produced surprising by-products. Therefore, theoretical calculations of global and local reactivity were performed based on Pearson's hard and soft acids and bases (HSAB) principle to understand the regioselectivity that occurred in the reduction of the olefinic carbons of the compounds. Local electrophilicity (ωk) was the most useful parameter for explaining the selectivity of the polar reactions. This local parameter was defined with the condensed Fukui function and redefined with the electrophilic (Pk+) Parr function. The similar patterns of both resulting sets of values helped to demonstrate the electrophilic behavior (soft acid) of the olefinic carbons in these compounds. The theoretical calculations, nuclear magnetic resonance, and resonance hybrids showed the moieties in each compound that are most susceptible to reduction.
Assuntos
Benzofuranos/química , Modelos Químicos , Oxirredução , Teoria Quântica , Benzofuranos/síntese química , Catálise , Técnicas de Química Sintética , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
BACKGROUND: Thalidomide, the first synthesized phthalimide, has demonstrated sedative- hypnotic and antiepileptic effects on the central nervous system. N-substituted phthalimides have an interesting chemical structure that confers important biological properties. OBJECTIVE: Non-chiral (ortho and para bis-isoindoline-1,3-dione, phthaloylglycine) and chiral phthalimides (N-substituted with aspartate or glutamate) were synthesized and the sedative, anxiolytic and anticonvulsant effects were tested. METHOD: Homology modeling and molecular docking were employed to predict recognition of the analogues by hNMDA and mGlu receptors. The neuropharmacological activity was tested with the open field test and elevated plus maze (EPM). The compounds were tested in mouse models of acute convulsions induced either by pentylenetetrazol (PTZ; 90 mg/kg) or 4-aminopyridine (4-AP; 10 mg/kg). RESULTS: The ortho and para non-chiral compounds at 562.3 and 316 mg/kg, respectively, decreased locomotor activity. Contrarily, the chiral compounds produced excitatory effects. Increased locomotor activity was found with S-TGLU and R-TGLU at 100, 316 and 562.3 mg/kg, and S-TASP at 316 and 562.3 mg/kg. These molecules showed no activity in the EPM test or PTZ model. In the 4-AP model, however, S-TGLU (237.1, 316 and 421.7 mg/kg) as well as S-TASP and R-TASP (316 mg/kg) lowered the convulsive and death rate. CONCLUSION: The chiral compounds exhibited a non-competitive NMDAR antagonist profile and the non-chiral molecules possessed selective sedative properties. The NMDAR exhibited stereoselectivity for S-TGLU while it is not a preference for the aspartic derivatives. The results appear to be supported by the in silico studies, which evidenced a high affinity of phthalimides for the hNMDAR and mGluR type 1.
Assuntos
Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Hipnóticos e Sedativos/farmacologia , Ftalimidas/farmacologia , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Humanos , Hipnóticos e Sedativos/síntese química , Hipnóticos e Sedativos/química , Ligantes , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Ftalimidas/síntese química , Ftalimidas/química , Receptores de Glutamato Metabotrópico/química , Receptores de N-Metil-D-Aspartato/química , Convulsões/tratamento farmacológico , EstereoisomerismoRESUMO
Dioxoisoindolines have been included as a pharmacophore group in diverse drug-like molecules with a wide range of biological activity. Various reports have shown that phthalimide derivatives are potent inhibitors of AChE, a key enzyme involved in the deterioration of the cholinergic system during the development of Alzheimer's disease. In the present study, 2-(2-(3,4-dimethoxyphenyl)ethyl)isoindoline-1,3-dione was synthesized, crystallized and evaluated as an AChE inhibitor. The geometric structure of the crystal and the theoretical compound (from molecular modeling) were analyzed and compared, finding a close correlation. The formation of the C6-H6···O19 interaction could be responsible for the non-negligible out of phenyl plane deviation of the C19 methoxy group, the O3 from the carbonyl group lead to C16-H16···O3i intermolecular interactions to furnish C(9) and C(14) infinite chains within the (- 4 0 9) and (- 3 1 1) families of planes. Finally, the biological experiments reveal that the isoindoline-1,3-dione exerts a good competitive inhibition on AChE (Ki = 0.33-0.93 mM; 95% confidence interval) and has very low acute toxicity (LD50 > 1600 mg/kg) compared to the AChE inhibitors currently approved for clinical use.
RESUMO
The inflammatory condition of malignant tumors continually exposes cancer cells to reactive oxygen species, an oxidizing condition that leads to the activation of the antioxidant defense system. A similar activation occurs with glutathione production. This oxidant condition enables tumor cells to maintain the energy required for growth, proliferation, and evasion of cell death. The objective of the present study was to determine the effect on hepatocellular carcinoma cells of a combination treatment with maleic anhydride derivatives (prooxidants) and quercetin (an antioxidant). The results show that the combination of a prooxidant/antioxidant had a cytotoxic effect on HuH7 and HepG2 liver cancer cells, but not on either of two normal human epithelial cell lines or on primary hepatocytes. The combination treatment triggered apoptosis in hepatocellular carcinoma cells by activating the intrinsic pathway and causing S phase arrest during cell cycle progression. There is also clear evidence of a modification in cytoskeletal actin and nucleus morphology at 24 and 48 h posttreatment. Thus, the current data suggest that the combination of two anticarcinogenic drugs, a prooxidant followed by an antioxidant, can be further explored for antitumor potential as a new treatment strategy.