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1.
Eur J Med Chem ; 236: 114329, 2022 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-35397400

RESUMO

The incorporation of the fluorine motif is a strategy widely applied in drug design for modulating the activity, physicochemical parameters, and metabolic stability of chemical compounds. In this study, we attempted to reduce the affinity for ether-à-go-go-related gene (hERG) channel by introducing fluorine atoms in a group of 1H-pyrrolo[3,2-c]quinolines that are capable of inhibiting monoamine oxidase type B (MAO-B). A series of structural modifications guided by in vitro evaluation of MAO-B inhibition and antitargeting for hERG channels were performed, which led to the identification of 1-(3-chlorobenzyl)-4-(4,4-difluoropiperidin-1-yl)-1H-pyrrolo[3,2-c]quinoline (26). Compound 26 acted as a reversible MAO-B inhibitor exhibiting selectivity over 45 targets, enzymes, transporters, and ion channels, and showed potent glioprotective properties in cultured astrocytes. In addition, the compound demonstrated good metabolic stability in rat liver microsomes assay, a favorable safety profile, and brain permeability. It also displayed procognitive effects in the novel object recognition test in rats and antidepressant-like activity in forced swim test in mice. The findings of the study suggest that reversible MAO-B inhibitors can have potential therapeutic applications in Alzheimer's disease.


Assuntos
Inibidores da Monoaminoxidase , Quinolinas , Animais , Encéfalo/metabolismo , Flúor/farmacologia , Camundongos , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Quinolinas/metabolismo , Ratos
2.
J Med Chem ; 64(2): 1180-1196, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33439019

RESUMO

G-protein coupled receptors (GPCRs) exist in an equilibrium of multiple conformational states, including different active states, which depend on the nature of the bound ligand. In consequence, different conformational states can initiate specific signal transduction pathways. The study identified compound 7e, which acts as a potent 5-hydroxytryptamine type 6 receptor (5-HT6R) neutral antagonist at Gs and does not impact neurite growth (process controlled by Cdk5). MD simulations highlighted receptor conformational changes for 7e and inverse agonist PZ-1444. In cell-based assays, neutral antagonists of the 5-HT6R (7e and CPPQ), but not inverse agonists (SB-258585, intepirdine, PZ-1444), displayed glioprotective properties against 6-hydroxydopamine-induced and doxorubicin-induced cytotoxicity. These suggest that targeting the activated conformational state of the 5-HT6R with neutral antagonists implicates the protecting properties of astrocytes. Additionally, 7e prevented scopolamine-induced learning deficits in the novel object recognition test in rats. We propose 7e as a probe for further understanding of the functional outcomes of different states of the 5-HT6R.


Assuntos
Imidazóis/síntese química , Imidazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Humanos , Deficiências da Aprendizagem/induzido quimicamente , Deficiências da Aprendizagem/prevenção & controle , Masculino , Conformação Molecular , Neuritos/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-Atividade
3.
Eur J Med Chem ; 208: 112765, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32949963

RESUMO

The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT6 receptor (5-HT6R) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking priviliged scaffolds of 5-HT6R with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HT6R at Gs signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay, artificial membrane permeability, no hepatotoxicity, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HT6R/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies.


Assuntos
Alcinos/farmacologia , Indóis/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Receptores de Serotonina/metabolismo , Alcinos/síntese química , Alcinos/farmacocinética , Animais , Astrócitos/efeitos dos fármacos , Linhagem Celular Tumoral , Agonismo Inverso de Drogas , Células HEK293 , Humanos , Indóis/síntese química , Indóis/farmacocinética , Masculino , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/farmacocinética , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacocinética , Nootrópicos/síntese química , Nootrópicos/farmacocinética , Ratos Sprague-Dawley , Ratos Wistar , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacocinética , Antagonistas da Serotonina/farmacologia , Relação Estrutura-Atividade
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