RESUMO
A series of oxadiazolone bioisosteres of pregabalin 1 and gabapentin 2 were prepared, and several were found to exhibit similar potency for the alpha(2)-delta subunit of voltage-gated calcium channels. Oxadiazolone 9 derived from 2 achieved low brain uptake but was nevertheless active in models of osteoarthritis. The high clearance associated with compound 9 was postulated to be a consequence of efflux by OAT and/or OCT, and was attenuated on co-administration with cimetidine or probenecid.
Assuntos
Aminas , Ácidos Cicloexanocarboxílicos , Osteoartrite/tratamento farmacológico , Oxidiazóis/química , Oxidiazóis/uso terapêutico , Ácido gama-Aminobutírico/análogos & derivados , Animais , Encéfalo/metabolismo , Interações Medicamentosas , Quimioterapia Combinada , Gabapentina , Fatores de Transcrição de Octâmero , Transportadores de Ânions Orgânicos , Oxidiazóis/farmacologia , Pregabalina , RatosRESUMO
We describe three novel regioisomeric series of aryl naphthyridine analogs, which are potent antagonists of the Class III GPCR mGlu5 receptor. The synthesis and in vitro and in vivo pharmacological activities of these analogs are discussed.
Assuntos
Naftiridinas/síntese química , Naftiridinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Cricetulus , Ratos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/fisiologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Pregabalin (Lyrica) is a novel amino acid compound that binds with high affinity to the alpha2-delta (alpha2-delta) auxiliary protein of voltage-gated calcium channels. In vivo, it potently prevents seizures, pain-related behaviors and has anxiolytic-like activity in rodent models. The present studies were performed to determine the profile of pregabalin anticonvulsant activity in a variety of mouse and rat models. In the high-intensity electroshock test, pregabalin potently inhibited tonic extensor seizures in rats (ED50 = 1.8 mg/kg, PO), and low-intensity electroshock seizures in mice. It prevented tonic extensor seizures in the DBA/2 audiogenic mouse model (ED50 = 2.7 mg/kg, PO). Its time course of action against electroshock induced seizures in rats roughly followed the pharmacokinetics of radiolabeled drug in the brain compartment. At higher dosages (ED50 1= 31 mg/kg, PO), pregabalin prevented clonic seizures from pentylenetetrazole in mice. In a kindled rat model of partial seizures, pregabalin prevented stages 4-5 behavioral seizures (lowest effective dose = 10 mg/kg, IP), and also reduced the duration of electrographic seizures. Pregabalin was not active to prevent spontaneous absence-like seizures in the Genetic Absence Epilepsy in Rats from Strasbourg (GAERS) inbred Wistar rat strain. Pregabalin caused ataxia and decreased spontaneous locomotor activity at dosages 10-30-fold higher than those active to prevent seizures. These findings suggest that pregabalin has an anticonvulsant mechanism different from the prototype antiepileptic drugs and similar to that of gabapentin except with increased potency and bioavailability. In summary, our results show that pregabalin has several properties that favor treatment of partial seizures in humans.
Assuntos
Anticonvulsivantes/farmacocinética , Comportamento Animal/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Convulsões/tratamento farmacológico , Ácido gama-Aminobutírico/análogos & derivados , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Epilepsia/metabolismo , Feminino , Marcha Atáxica/tratamento farmacológico , Marcha Atáxica/metabolismo , Excitação Neurológica , Masculino , Camundongos , Camundongos Endogâmicos , Atividade Motora/efeitos dos fármacos , Pregabalina , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/metabolismo , Ácido gama-Aminobutírico/administração & dosagem , Ácido gama-Aminobutírico/efeitos adversos , Ácido gama-Aminobutírico/farmacocinéticaRESUMO
Pregabalin exhibits robust activity in preclinical assays indicative of potential antiepileptic, anxiolytic, and antihyperalgesic clinical efficacy. It binds with high affinity to the alpha(2)-delta subunit of voltage-gated calcium channels and is a substrate of the system L neutral amino acid transporter. A series of pregabalin analogues were prepared and evaluated for their alpha(2)-delta binding affinity as demonstrated by their ability to inhibit binding of [(3)H]gabapentin to pig brain membranes and for their potency to inhibit the uptake of [(3)H]leucine into CHO cells, a measure of their ability to compete with the endogenous substrate at the system L transporter. Compounds were also assessed in vivo for their ability to promote anxiolytic, analgesic, and anticonvulsant actions. These studies suggest that distinct structure activity relationships exist for alpha(2)-delta binding and system L transport inhibition. However, both interactions appear to play an important role in the in vivo profile of these compounds.
Assuntos
Sistema L de Transporte de Aminoácidos/metabolismo , Analgésicos/síntese química , Ansiolíticos/síntese química , Anticonvulsivantes/síntese química , Canais de Cálcio/metabolismo , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/síntese química , Aminas/antagonistas & inibidores , Aminas/metabolismo , Analgésicos/química , Analgésicos/farmacologia , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Ácidos Cicloexanocarboxílicos/antagonistas & inibidores , Ácidos Cicloexanocarboxílicos/metabolismo , Gabapentina , Técnicas In Vitro , Leucina/antagonistas & inibidores , Leucina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Pregabalina , Ligação Proteica , Subunidades Proteicas/metabolismo , Ratos , Relação Estrutura-Atividade , Suínos , Ácido gama-Aminobutírico/química , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/farmacologiaRESUMO
As part of a program aimed at generating compounds with affinity for the alpha(2)-delta subunit of voltage-gated calcium channels, several novel beta-amino acids were prepared using an efficient nitroalkane-mediated cyclopropanation as a key step. Depending on the ester that was chosen, the target amino acids could be prepared in as few as three steps. The cyclopropyl amino acids derived from ketones proved to be potent binders of the alpha(2)-delta subunit of voltage-gated calcium channels, but did not interact with the large neutral amino acid system L (leucine) transporter. Anticonvulsant effects were observed in vivo with compound 34 but only after intracerebroventricular (icv) administration, presumably due to inadequate brain concentrations of the drug being achieved following oral dosing. However, pregabalin 1 was active in the DBA/2 model after oral (and icv) dosing, supporting a hypothesis that active transport is a prerequisite for such zwitterionic species to cross the blood-brain barrier.
Assuntos
Aminas/síntese química , Aminoácidos/química , Canais de Cálcio/efeitos dos fármacos , Ácidos Cicloexanocarboxílicos/síntese química , Ciclopropanos/síntese química , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/síntese química , Administração Oral , Aminas/química , Aminas/farmacologia , Sistema L de Transporte de Aminoácidos/metabolismo , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Transporte Biológico Ativo , Barreira Hematoencefálica/metabolismo , Células CHO , Canais de Cálcio/metabolismo , Cricetinae , Cricetulus , Ciclização , Ácidos Cicloexanocarboxílicos/química , Ácidos Cicloexanocarboxílicos/farmacologia , Ciclopropanos/química , Ciclopropanos/farmacologia , Gabapentina , Técnicas In Vitro , Injeções Intraventriculares , Ativação do Canal Iônico , Masculino , Camundongos , Camundongos Endogâmicos DBA , Nitrilas/química , Pregabalina , Subunidades Proteicas/metabolismo , Ratos , Ratos Sprague-Dawley , Suínos , Ácido gama-Aminobutírico/química , Ácido gama-Aminobutírico/farmacologiaRESUMO
A novel series of potent 2-aryl pyrido[2,3-d]pyrimidine mGlu5 receptor antagonists are described. The synthesis and pharmacological activities of these analogs are discussed.
Assuntos
Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Células CHO , Cálcio/metabolismo , Cricetinae , Cricetulus , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Indicadores e Reagentes , Articulações/patologia , Lactonas/uso terapêutico , Osteoartrite/induzido quimicamente , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Piridinas/química , Piridinas/farmacologia , Ratos , Receptor de Glutamato Metabotrópico 5 , Relação Estrutura-Atividade , Sulfonas/uso terapêuticoRESUMO
Rational replacement of the alkyne linker of mGluR5 antagonist MPEP gave 7-arylquinolines. SAR optimization gave an orally active compound with high affinity for the MPEP binding site.
Assuntos
Desenho de Fármacos , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Modelos Moleculares , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Receptor de Glutamato Metabotrópico 5 , Relação Estrutura-AtividadeRESUMO
Several beta-amino tetrazole analogs of gabapentin 1 and pregabalin 2 were prepared by one of two convergent, highly efficient routes, and their affinity for the alpha(2)-delta protein examined. Two select compounds with potent affinity for alpha(2)-delta, 8a and 16a, were subsequently tested in vivo in an audiogenic seizure model and found to elicit protective effects.
Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Ácidos Carboxílicos/química , Epilepsia Reflexa/prevenção & controle , Ácido gama-Aminobutírico/análogos & derivados , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Animais , Anticonvulsivantes/química , Sítios de Ligação , Ácidos Cicloexanocarboxílicos/síntese química , Ácidos Cicloexanocarboxílicos/química , Ácidos Cicloexanocarboxílicos/farmacologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Gabapentina , Camundongos , Camundongos Endogâmicos DBA , Estrutura Molecular , Pregabalina , Subunidades Proteicas/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Ácido gama-Aminobutírico/síntese química , Ácido gama-Aminobutírico/química , Ácido gama-Aminobutírico/farmacologiaRESUMO
A series of carboxylate bioisosteres of structures related to gabapentin 1 have been prepared. When the carboxylate was replaced by a tetrazole, this group was recognized by the alpha2-delta protein. Further characterization of alpha2-delta binding compounds 14a and 14b revealed a similar pattern of functional in vitro and in vivo activity to gabapentin 1.