RESUMO
INTRODUCTION: Epilepsy is a common neurological disorder; however, its therapy is not satisfactory because a large number of patients suffer from refractory seizures and/or has a low quality of life due to antiepileptic drug (AED) side effects. Glutamate is the major excitatory neurotransmitter in the brain, AMPA receptors (AMPARs) represent a validated target for AEDs' development. Evidences support their role during seizures and neurodegeneration. Development of AMPAR ligands has led to two different branches of research, with the identification of competitive and noncompetitive antagonists. AREAS COVERED: We herein describe the architecture of AMPAR and the main structure-activity relationships of antagonists. Finally, we report the effects of AMPAR antagonists in preclinical models and clinical trials in epileptic patients. We reviewed the most relevant research in the field, focusing on research advances for the oldest AMPA antagonists and the new most promising molecules identified. EXPERT OPINION: Overall, the development of AMPAR antagonists confirms their great clinical potential; their arrival to clinical practice has been slowed down by their unfavorable pharmacokinetic profile and tolerability; however, their clinical use might be justified by their efficacy and the new drugs developed such as perampanel have been greatly ameliorated from both points of view.
Assuntos
Anticonvulsivantes/farmacologia , Epilepsia/tratamento farmacológico , Receptores de AMPA/antagonistas & inibidores , Animais , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/química , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Epilepsia/fisiopatologia , Humanos , Receptores de AMPA/metabolismo , Relação Estrutura-AtividadeRESUMO
We have identified 1H-benzylindole analogues as a novel series of human immunodeficiency virus (HIV) integrase inhibitors with antiretroviral activities against different strains of HIV type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strain MAC(251) [SIV(MAC(251))]. Molecular modeling and structure-activity relationship-based optimization resulted in the identification of CHI/1043 as the most potent congener. CHI/1043 inhibited the replication of HIV-1(III(B)) in MT-4 cells at a 50% effective concentration (EC(50)) of 0.60 microM, 70-fold below its cytotoxic concentration. Equal activities against HIV-1(NL4.3), HIV-2(ROD), HIV-2(EHO), and SIV(MAC(251)) were observed. CHI/1043 was equally active against virus strains resistant against inhibitors of reverse transcriptase or protease. Replication of both X4 and R5 strains in peripheral blood mononuclear cells was sensitive to the inhibitory effect of CHI/1043 (EC(50), 0.30 to 0.38 microM). CHI/1043 inhibited integrase strand transfer activity in oligonucleotide-based enzymatic assays at low micromolar concentrations. Time-of-addition experiments confirmed CHI/1043 to interfere with the viral replication cycle at the time of retroviral integration. Quantitative Alu PCR corroborated that the anti-HIV activity is based upon the inhibition of proviral DNA integration. An HIV-1 strain selected for 70 passages in the presence of CHI/1043 was evaluated genotypically and phenotypically. The mutations T66I and Q146K were present in integrase. Cross-resistance to other integrase strand transfer inhibitors, such as L-708,906, the naphthyridine analogue L-870,810, and the clinical drugs GS/9137 and MK-0518, was observed. In adsorption, distribution, metabolism, excretion, and toxicity studies, antiviral activity was strongly reduced by protein binding, and metabolization in human liver microsomes was observed. Transport studies with Caco cells suggest a low oral bioavailability.
Assuntos
Inibidores de Integrase de HIV/farmacologia , HIV/efeitos dos fármacos , Indóis/farmacologia , Integrases/metabolismo , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Células CACO-2 , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Ensaio de Imunoadsorção Enzimática , HIV/enzimologia , HIV/genética , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Humanos , Indóis/síntese química , Indóis/química , Integrases/genética , Estrutura Molecular , Reação em Cadeia da Polimerase , Proteínas Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
In our studies on the development of new anticonvulsants, we planned the synthesis of N-substituted 1,2,3,4-tetrahydroisoquinolines to explore the structure-activity relationships. All derivatives were evaluated against audiogenic seizures in DBA/2 mice, and the 1-(4'-bromophenyl)-6,7-dimethoxy-2-(piperidin-1-ylacetyl) derivative (26) showed the highest activity with a potency comparable to that of talampanel, the only noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist in clinical trials as an anticonvulsant agent. Electrophysiological experiments indicated that 26 acts as noncompetitive AMPA receptor modulator.
Assuntos
Anticonvulsivantes/síntese química , Isoquinolinas/síntese química , Piperidinas/síntese química , Tetra-Hidroisoquinolinas/síntese química , Estimulação Acústica , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Técnicas In Vitro , Isoquinolinas/química , Isoquinolinas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Condutos Olfatórios/efeitos dos fármacos , Condutos Olfatórios/fisiologia , Piperidinas/química , Piperidinas/farmacologia , Ratos , Ratos Wistar , Receptores de AMPA/efeitos dos fármacos , Receptores de AMPA/fisiologia , Convulsões/etiologia , Convulsões/prevenção & controle , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologiaRESUMO
A 3D pharmacophore model predicting anticonvulsant activity was obtained for a series of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives recently disclosed as a new class of noncompetitive AMPA receptor antagonists. The training set included 17 compounds with varying potency against audiogenic seizures in DBA/2 mice. The best statistical hypothesis, generated with the HypoGen module of Catalyst 4.9, consisted of five features: two hydrogen bond acceptors, two hydrophobic features, and one hydrophobic aromatic region, providing a model with a correlation coefficient of 0.919. The obtained model was an efficient tool in the design of some new anticonvulsant agents containing the tetrahydroisoquinoline scaffold. Moreover, in order to explain the different degree of efficacy of the newly designed N-substituted derivatives, excluded volumes were also considered.
Assuntos
Anticonvulsivantes/química , Modelos Moleculares , Tetra-Hidroisoquinolinas/química , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Benzodiazepinas/uso terapêutico , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Epilepsia Reflexa/induzido quimicamente , Epilepsia Reflexa/prevenção & controle , Feminino , Isoquinolinas/química , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos DBA , Modelos Animais , Conformação Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/farmacologia , Tetra-Hidroisoquinolinas/uso terapêuticoRESUMO
We describe the use of pharmacophore modeling as an efficient tool in the discovery of novel HIV-1 integrase (IN) inhibitors. A three-dimensional hypothetical model for the binding of diketo acid analogues to the enzyme was built by means of the Catalyst program. Using these models as a query for virtual screening, we found several compounds that contain the specified 3D patterns of chemical functions. Biological testing shows that our strategy was successful in searching for new structural leads as HIV-1 IN inhibitors.
Assuntos
Avaliação Pré-Clínica de Medicamentos/estatística & dados numéricos , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Simulação por Computador , DNA Viral/efeitos dos fármacos , DNA Viral/genética , Bases de Dados Factuais , Desenho de Fármacos , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/genética , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Interface Usuário-ComputadorRESUMO
As a follow up of our previous structure-activity relationship and molecular modeling studies, we synthesized a novel series of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as potential non-competitive AMPA receptor antagonists. When tested for their ability to prevent sound-induced seizures in DBA/2 mice, some of these novel compounds showed high anticonvulsant potency.
Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Convulsões/prevenção & controle , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/farmacologia , Animais , Benzodiazepinas/farmacologia , Benzodiazepinonas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos DBA , Modelos Moleculares , Estrutura Molecular , Receptores de AMPA/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Several 2,3-diaryl-1,3-thiazolidin-4-ones were synthesized and evaluated as anti-HIV agents. The results of the in vitro tests showed that some of them were highly effective inhibitors of HIV-1 replication at 30-50 nM concentrations with minimal cytotoxicity, thereby acting as non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs).
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Avaliação Pré-Clínica de Medicamentos , HIV-1/efeitos dos fármacos , HIV-1/crescimento & desenvolvimento , HIV-2/efeitos dos fármacos , HIV-2/crescimento & desenvolvimento , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/virologia , Replicação Viral/efeitos dos fármacosRESUMO
The anticonvulsant activities of some 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA)/kainate receptor antagonists, noncompetitive (2,3-benzodiazepines) and a competitive 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline (NBQX), were compared in different experimental seizure models. In particular, compounds were evaluated against audiogenic seizure in DBA/2 mice, maximal electroshock seizure (MES) test and various chemoconvulsant models; both groups showed a protective action against audiogenic seizure, MES- and pentylenetetrazole (PTZ)-induced seizures. All 2,3-benzodiazepines were also protective against clonic and tonic seizures and lethality induced by 4-aminopyridine, kainate, AMPA and 3-mercaptopropionic acid but were ineffective against NMDA-induced seizures. NBQX was unable to affect 4-aminopyridine-, mercaptopropionic acid- and NMDA-induced seizures. The duration of anticonvulsant action of 33 micromol/kg of some 2,3-benzodiazepine in DBA/2 mice, genetically susceptible to audiogenic seizures, was also investigated. The derivatives possessing a thiocarbonyl group at the C-4 position of heptatomic ring showed higher anticonvulsant activities and longer lasting protective effects. We conclude that all 2,3-benzodiazepines studied are effective against various models of experimental epilepsy and the presence of thiocarbonyl groups at the C-4 position of heptatomic ring is able to increase the anticonvulsant effect of these compounds.
Assuntos
Anticonvulsivantes/uso terapêutico , Benzodiazepinas/química , Benzodiazepinas/uso terapêutico , Modelos Animais de Doenças , Estimulação Acústica/métodos , Animais , Relação Dose-Resposta a Droga , Eletrochoque/métodos , Epilepsia Reflexa/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos DBA , Camundongos Endogâmicos ICR , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológicoRESUMO
N-Acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized as potential noncompetitive AMPA receptor antagonists on the basis of molecular modeling studies. Sound-induced seizure testing showed that this class of compounds possessed anticonvulsant properties. In particular, 10c was more potent than talampanel (2), a noncompetitive AMPA receptor antagonist currently being investigated in phase III trials as an antiepileptic agent. Furthermore, electrophysiological studies indicated that 10c was a highly effective noncompetitive-type modulator of the AMPA receptor.