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1.
BMC Neurosci ; 16: 67, 2015 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-26480871

RESUMO

BACKGROUND: Synaptic dysfunction is a key event in pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) where synapse loss pathologically correlates with cognitive decline and dementia. Although evidence suggests that aberrant protein production and aggregation are the causative factors in familial subsets of such diseases, drugs singularly targeting these hallmark proteins, such as amyloid-ß, have failed in late stage clinical trials. Therefore, to provide a successful disease-modifying compound and address synaptic dysfunction and memory loss in AD and mixed pathology dementia, we repurposed a clinically proven drug, CMZ, with neuroprotective and anti-inflammatory properties via addition of nitric oxide (NO) and cGMP signaling property. RESULTS: The novel compound, NMZ, was shown to retain the GABAA potentiating actions of CMZ in vitro and sedative activity in vivo. Importantly, NMZ restored LTP in hippocampal slices from AD transgenic mice, whereas CMZ was without effect. NMZ reversed amnestic blockade of acetylcholine receptors by scopolamine as well as NMDA receptor blockade by a benzodiazepine and a NO synthase inhibitor in the step-through passive avoidance (STPA) test of learning and working memory. A PK/PD relationship was developed based on STPA analysis coupled with pharmacokinetic measures of drug levels in the brain: at 1 nM concentration in brain and plasma, NMZ was able to restore memory consolidation in mice. CONCLUSION: Our findings show that NMZ embodies a promising pharmacological approach targeting synaptic dysfunction and opens new avenues for neuroprotective intervention strategies in mixed pathology AD, neurodegeneration, and dementia.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Clormetiazol/análogos & derivados , Reposicionamento de Medicamentos/métodos , Agonistas de Receptores de GABA-A/farmacologia , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Animais , Proteína de Ligação a CREB/metabolismo , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Agonistas de Receptores de GABA-A/farmacocinética , Masculino , Camundongos , Camundongos Transgênicos , Fármacos Neuroprotetores/farmacocinética , Óxido Nítrico/metabolismo , Nootrópicos/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/patologia , Xenopus laevis
2.
ACS Med Chem Lett ; 2(9): 656-661, 2011 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-21927645

RESUMO

Hybrid nitrate drugs have been reported to provide NO bioactivity to ameliorate side effects or to provide ancillary therapeutic activity. Hybrid nitrate selective serotonin reuptake inhibitors (NO-SSRIs) were prepared to improve the therapeutic profile of this drug class. A synthetic strategy for use of a thiocarbamate linker was developed, which in the case of NO-fluoxetine facilitated hydrolysis to fluoxetine at pH 7.4 within 7 hours. In cell culture, NO-SSRIs were weak inhibitors of the serotonin transporter, however, in the forced swimming task (FST) in rats, NO-fluoxetine demonstrated classical antidepressant activity. Comparison of NO-fluoxetine, with fluoxetine, and an NO-chimera nitrate developed for Alzheimer's disease (GT-1061), was made in the step through passive avoidance (STPA) test of learning and memory in rats treated with scopolamine as an amnesic agent. Fluoxetine was inactive, whereas NO-fluoxetine and GT-1061 both restored long-term memory. GT-1061 also produced antidepressant behavior in FST. These data support the potential for NO-SSRIs to overcome the lag in onset of therapeutic action and provide co-therapy of neuropathologies concomitant with depression.

3.
ChemMedChem ; 2(10): 1520-6, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17654759

RESUMO

The search for the "ideal" selective estrogen receptor modulator (SERM) as a substitute for hormone replacement therapy (HRT) or use in cancer chemoprevention has focused on optimization of estrogen receptor (ER) ligand binding. Based on the clinical and preclinical benzothiophene SERMs, raloxifene and arzoxifene, a family of SERMs has been developed to modulate activity and oxidative lability. Antiestrogenic potency measured in human endometrial and breast cancer cells, and ER ligand binding data were correlated and seen to provide a guide to SERM design only when viewed in toto. The in vitro studies were extended to the juvenile rat model, in which the desired antiestrogenic profile and putative cardiovascular benefits of SERMs were observed.


Assuntos
Piperidinas/farmacologia , Cloridrato de Raloxifeno/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Tiofenos/farmacologia , Animais , Feminino , Lipídeos/sangue , Tamanho do Órgão/efeitos dos fármacos , Piperidinas/química , Cloridrato de Raloxifeno/química , Ratos , Ratos Sprague-Dawley , Receptores de Estrogênio/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/química , Relação Estrutura-Atividade , Tiofenos/química , Útero/efeitos dos fármacos
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