RESUMO
Retinitis pigmentosa (RP) is an inherited retinal dystrophy that courses with progressive degeneration of retinal tissue and loss of vision. Currently, RP is an unpreventable, incurable condition. We propose glycogen synthase kinase 3 (GSK-3) inhibitors as potential leads for retinal cell neuroprotection, since the retina is also a part of the central nervous system and GSK-3 inhibitors are potent neuroprotectant agents. Using a chemical genetic approach, diverse small molecules with different potency and binding mode to GSK-3 have been used to validate and confirm GSK-3 as a pharmacological target for RP. Moreover, this medicinal chemistry approach has provided new leads for the future disease-modifying treatment of RP.
Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Retinose Pigmentar/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Retinose Pigmentar/enzimologia , Retinose Pigmentar/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
Leucine-rich repeat kinase 2 (LRRK2) is a protein kinase whose activity plays an important role in neurodegenerative diseases. Although mutations in LRRK2 gene are the most common cause of monogenic Parkinson's disease, it has been reported that LRRK2 may promote Tau phosphorylation, increasing its aggregation. Thus, the modulation of LRRK2 activity by small molecules able to inhibit this kinase activity could be an innovative therapeutic strategy for different tauopathies. We examined the therapeutic effects of a new benzothiazole-based LRRK2 inhibitor, known as JZ1.40, in a mouse model of tauopathy. Mice were injected in the right hippocampus with an adeno-associated vector expressing human-TAUP301L and treated daily with JZ1.40 (10 mg/kg, i.p) or vehicle for three weeks. JZ1.40 reaches the brain and modulates RAB10 and Tau phosphorylation at the epitopes modified by LRRK2. Moreover, JZ1.40 treatment ameliorates the cognitive impairment induced by TAUP301L overexpression, which correlates with prevention of granular cell layer degeneration by improving synaptic plasticity. These data show that JZ1.40 is neuroprotective in vivo, which is translated into cognition enhancement.
Assuntos
Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Fármacos Neuroprotetores , Tauopatias/tratamento farmacológico , Tauopatias/prevenção & controle , Proteínas tau/metabolismo , Animais , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/genética , Modelos Animais de Doenças , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Mutação , Plasticidade Neuronal/efeitos dos fármacos , Fosforilação/genética , Tauopatias/metabolismo , Tauopatias/psicologia , Proteínas rab de Ligação ao GTP/metabolismoRESUMO
Leucine rich repeat kinase 2 (LRRK2) is an enigmatic enzyme and a relevant target for Parkinson's disease (PD). However, despite the significant amount of research done in the past decade, the precise function of LRRK2 remains largely unknown. Moreover, the therapeutic potential of its inhibitors is in its infancy with the first clinical trial having just started. In the present work, the molecular mechanism of LRRK2 in the control of neurogenesis or gliogenesis was investigated. We designed and synthesized novel benzothiazole-based LRRK2 inhibitors and showed that they can modulate the Wnt/ß-catenin signaling pathway. Furthermore, compounds 5 and 14 were able to promote neural progenitors proliferation and drive their differentiation toward neuronal and oligodendrocytic cell fates. These results suggest potential new avenues for the application of LRRK2 inhibitors in demyelinating diseases in which oligodendrocyte cell-death is one of the pathological features.
Assuntos
Benzotiazóis/farmacologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Oligodendroglia/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Benzotiazóis/química , Células Cultivadas , Feminino , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Neurogênese/efeitos dos fármacos , Oligodendroglia/citologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Inibidores de Proteínas Quinases/químicaRESUMO
Aim: Due to the urgent need for effective drugs to treat schistosomiasis that act through a known molecular mechanism of action, we focused on a target-based approach with the aim to discover inhibitors of a cyclic nucleotide phosphodiesterase from Schistosoma mansoni (SmPDE4A). Materials & methods: To discover new inhibitors of SmPDE4A homology models of the enzyme structure were constructed based on known human and protozoan homologs. The best two models were selected for subsequent virtual screening of our in-house chemical library. Results & conclusion: A total of 25 library compounds were selected for experimental confirmation as SmPDE4A inhibitors and after dose-response experiments, three top hits were identified. The results presented validate the virtual screening approach to identify new inhibitors for clinically relevant phosphodiesterases.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Descoberta de Drogas , Inibidores da Fosfodiesterase 4/farmacologia , Schistosoma mansoni/enzimologia , Esquistossomose/tratamento farmacológico , Animais , Relação Dose-Resposta a Droga , Modelos Moleculares , Estrutura Molecular , Inibidores da Fosfodiesterase 4/química , Esquistossomose/metabolismo , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Retinitis pigmentosa (RP) is a group of hereditary retinal neurodegenerative conditions characterized by primary dysfunction and death of photoreceptor cells, resulting in visual loss and, eventually, blindness. To date, no effective therapies have been transferred to clinic. Given the diverse genetic etiology of RP, targeting common cellular and molecular retinal alterations has emerged as a potential therapeutic strategy. METHODS: Using the Pde6b rd10/rd10 mouse model of RP, we investigated the effects of daily intraperitoneal administration of VP3.15, a small-molecule heterocyclic GSK-3 inhibitor. Gene expression was analyzed by quantitative PCR and protein expression and phosphorylation by Western blot. Photoreceptor preservation was evaluated by histological analysis and visual function was assessed by electroretinography. RESULTS: In rd10 retinas, increased expression of pro-inflammatory markers and reactive gliosis coincided with the early stages of retinal degeneration. Compared with wild-type controls, GSK-3ß expression (mRNA and protein) remained unchanged during the retinal degeneration period. However, levels of GSK-3ßSer9 and its regulator AktSer473 were increased in rd10 versus wild-type retinas. In vivo administration of VP3.15 reduced photoreceptor cell loss and preserved visual function. This neuroprotective effect was accompanied by a decrease in the expression of neuroinflammatory markers. CONCLUSIONS: These results provide proof of concept of the therapeutic potential of VP3.15 for the treatment of retinal neurodegenerative conditions in general, and RP in particular.
Assuntos
Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Retinose Pigmentar/patologia , Tiadiazóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Retina/efeitos dos fármacosRESUMO
Several findings propose the altered tau protein network as an important target for Alzheimer's disease (AD). Particularly, two points of pharmacological intervention can be envisaged: inhibition of phosphorylating tau kinase GSK-3ß and tau aggregation process. On the basis of this consideration and on our interest in multitarget paradigms in AD, we report on the discovery of 2,4-thiazolidinedione derivatives endowed with such a profile. 28 and 30 displayed micromolar IC50 values toward GSK-3ß, together with the capacity of inhibiting AcPHF6 aggregation of 60% and 80% at 10 µM, respectively. In addition, they showed PAMPA-BBB permeability, together with a suitable cellular safety profile. 30 also displayed inhibition of both K18 and full-length tau aggregations. Finally, both compounds were able to improve cell viability in an okadaic acid-induced neurodegeneration cell model. To the best of our knowledge, 28 and 30 are the first balanced, nontoxic, dual-acting compounds hitting tau cascade at two different hubs.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas tau/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/efeitos adversos , Fármacos do Sistema Nervoso Central/química , Fármacos do Sistema Nervoso Central/farmacologia , Dicroísmo Circular , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Transferência Ressonante de Energia de Fluorescência , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Células Hep G2 , Humanos , Microscopia de Força Atômica , Terapia de Alvo Molecular/métodos , Ácido Okadáico/toxicidade , Fosforilação/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade , Suínos , Tiazolidinedionas/química , Proteínas tau/antagonistas & inibidoresRESUMO
The discovery of haloperidol catalyzed a breakthrough in our understanding of the biochemical basis of schizophrenia, improved the treatment of psychosis, and facilitated deinstitutionalization. In doing so, it solidified the role for chemical neuroscience as a means to elucidate the molecular underpinnings of complex neuropsychiatric disorders. In this Review, we will cover aspects of haloperidol's synthesis, manufacturing, metabolism, pharmacology, approved and off-label indications, and adverse effects. We will also convey the fascinating history of this classic molecule and the influence that it has had on the evolution of neuropsychopharmacology and neuroscience.
Assuntos
Antipsicóticos , Doenças do Sistema Nervoso Central/tratamento farmacológico , Haloperidol , Neurociências , Animais , Antipsicóticos/química , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Haloperidol/química , Haloperidol/farmacologia , Haloperidol/uso terapêutico , HumanosRESUMO
Leucine-rich repeat kinase 2 (LRRK2) is one of the most pursued targets for Parkinson's disease (PD) therapy. Moreover, it has recently described its role in regulating Wnt signaling and thus, it may be involved in adult neurogenesis. This new hypothesis could give rise to double disease-modifying agents firstly by the benefits of inhibiting LRRK2 and secondly by promoting adult neurogenesis. Herein we report, the design, synthesis, biological evaluation, SAR and potential binding mode of indoline-like LRRK2 inhibitors and their preliminary neurogenic effect in neural precursor cells isolated from adult mice ventricular-subventricular zone. These results open new therapeutic horizons for the use of LRRK2 inhibitors as neuroregenerative agents. Moreover, the indolinone derivatives here prepared, inhibitors of the kinase activity of LRRK2, may be considered as pharmacological probes to study the potential neuroregeneration of the damaged brain.