RESUMO
The simpler, the better: H(3) histamine receptor (H(3)R) are of interest as therapeutic targets in cognitive and somnolence disorders. Here, lead optimization of H(3)R inverse agonists bearing a thiazolo[5,4-c]piperidine group gave rise to a clinical candidate with a much simpler unprecedented benzamide scaffold, displaying decreased hERG activity while maintaining high brain receptor occupancies.
Assuntos
Agonistas dos Receptores Histamínicos/química , Agonistas dos Receptores Histamínicos/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Receptores Histamínicos H3/metabolismo , Animais , Benzamidas/química , Benzamidas/farmacocinética , Benzamidas/farmacologia , Células CACO-2 , Agonistas dos Receptores Histamínicos/farmacocinética , Humanos , Masculino , Piperidinas/farmacocinética , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacocinética , Tiazóis/farmacologia , Transativadores/metabolismo , Regulador Transcricional ERGAssuntos
Antidepressivos/farmacologia , Cognição/efeitos dos fármacos , Receptores Histamínicos H3/metabolismo , Tiazóis/farmacologia , Animais , Antidepressivos/síntese química , Antidepressivos/química , Desenho de Fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaAssuntos
Benzeno/química , Antagonistas dos Receptores Histamínicos/química , Oxazóis/química , Pirrolidinas/química , Receptores Histamínicos H3/química , Animais , Células CACO-2 , Linhagem Celular , Transtornos Cognitivos/tratamento farmacológico , Agonismo Inverso de Drogas , Humanos , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Oxazóis/farmacocinética , Pirrolidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos H3/metabolismo , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacocinéticaRESUMO
PURPOSE: Synaptic vesicle protein 2A (SV2A) constitutes a distinct binding site for an antiepileptic drug levetiracetam (Keppra). In the present study we characterized SV2A (+/-) heterozygous mice in several seizure models and tested if the anticonvulsant efficacy of levetiracetam is reduced in these mice. METHODS: Seizure thresholds of male SV2A (+/-) mice and their wild-type littermates were assessed in pilocarpine (i.p.), kainic acid (s.c.), pentylenetetrazol (i.v.), 6-Hz and maximal electroshock models. Kindling development was compared in amygdala and corneal kindling models. Ex vivo binding of levetiracetam to SV2A was also performed. RESULTS: Long-term electroencephalography (EEG) monitoring and behavioral observations of SV2A (+/-) mice did not reveal any spontaneous seizure activity. However, a reduced seizure threshold of SV2A (+/-) mice was observed in pilocarpine, kainic acid, pentylenetetrazol, and 6-Hz models, but not in maximal electroshock seizure model. Accelerated epileptogenesis development was also demonstrated in amygdala and corneal kindling models. Anticonvulsant efficacy of levetiracetam, defined as its ability to increase seizure threshold for 6 Hz electrical stimulation, was significantly reduced (approx. 50%) in the SV2A (+/-) mice, consistently with reduced binding to SV2A in these mice. In contrast, valproate produced the same anticonvulsant effect in both SV2A (+/+) and SV2A (+/-) mice. DISCUSSION: The present results evidence that SV2A is involved in mediation of the in vivo anticonvulsant activity of levetiracetam, in accordance with its previously proposed mechanism of action. Furthermore, the present data also indicate that even partial SV2A deficiency may lead to increased seizure vulnerability and accelerated epileptogenesis.
Assuntos
Anticonvulsivantes/farmacologia , Epilepsia/genética , Glicoproteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Piracetam/análogos & derivados , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiologia , Animais , Sítios de Ligação/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Eletrochoque/estatística & dados numéricos , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Ácido Caínico , Excitação Neurológica/efeitos dos fármacos , Excitação Neurológica/genética , Excitação Neurológica/fisiologia , Levetiracetam , Masculino , Glicoproteínas de Membrana/farmacologia , Glicoproteínas de Membrana/fisiologia , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/farmacologia , Proteínas do Tecido Nervoso/fisiologia , Pentilenotetrazol/farmacologia , Farmacogenética , Fenótipo , Piracetam/farmacologiaRESUMO
Despite the increasing implication of the permeability transition pore (PTP) in the pathophysiology of neurodegenerative diseases, few selective PTP inhibitors have been reported so far. Here, we evaluate the pharmacological properties of a novel PTP inhibitor, BBMP (5-(benzylsulfonyl)-4-bromo-2-methyl-3(2H)-pyridazinone). This drug was discovered from the screening of a compound library against the PTP using a functional assay with isolated mitochondria. Similarly to cyclosporin A, the drug prevented Ca2+-induced permeability transition and mitochondrial depolarization. BBMP appeared more potent that minocycline in both swelling and membrane potential assays displaying pIC50 values of 5.5+/-0.1 and 5.6+/-0.0, respectively. Unlike minocycline, BBMP dose-dependently prevented DNA fragmentation induced by KCl 25/5 mM shift and serum deprivation in cerebellar granule neurons with a pIC50 of 5.7+/-0.6. The inhibition of PTP-mediated cytochrome c release observed in isolated mitochondria at 10 and 100 microM may explain its neuroprotective properties in vitro. These data suggest that the mitochondrial PTP is potentially involved in neuronal cell death and that PTP inhibitors, like BBMP, may possess a therapeutic potential in neurodegenerative disorders.
