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1.
J Med Chem ; 63(8): 4133-4154, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32233403

RESUMO

Fluorescently labeled dibenzodiazepinone-type muscarinic acetylcholine receptor (MR) antagonists, including dimeric ligands, were prepared using red-emitting cyanine dyes. Probes containing a fluorophore with negative charge showed high M2R affinities (pKi (radioligand competition binding): 9.10-9.59). Binding studies at M1 and M3-M5 receptors indicated a M2R preference. Flow cytometric and high-content imaging saturation and competition binding (M1R, M2R, and M4R) confirmed occupation of the orthosteric site. Confocal microscopy revealed that fluorescence was located mainly at the cell membrane (CHO-hM2R cells). Results from dissociation and saturation binding experiments (M2R) in the presence of allosteric M2R modulators (dissociation: W84, LY2119620, and alcuronium; saturation binding: W84) were consistent with a competitive mode of action between the fluorescent probes and the allosteric ligands. Taken together, these lines of evidence indicate that these ligands are useful fluorescent molecular tools to label the M2R in imaging and binding studies and suggest that they have a dualsteric mode of action.


Assuntos
Corantes Fluorescentes/metabolismo , Antagonistas Muscarínicos/metabolismo , Ftalimidas/metabolismo , Compostos de Amônio Quaternário/metabolismo , Receptor Muscarínico M2/antagonistas & inibidores , Receptor Muscarínico M2/metabolismo , Animais , Células CHO , Colinérgicos/química , Colinérgicos/metabolismo , Colinérgicos/farmacologia , Cricetulus , Corantes Fluorescentes/química , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacologia , Ftalimidas/química , Ftalimidas/farmacologia , Estrutura Secundária de Proteína , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia
2.
Org Biomol Chem ; 17(35): 8166-8174, 2019 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-31464336

RESUMO

Continuous flow-flash synthesis of a 2-bromobenzaldehyde derivative 18 as a key intermediate of a novel cholinergic muscarinic M1 positive allosteric modulator 1 bearing an isoindolin-1-one ring system as a pharmacophore has been achieved using flow microreactors through selective I/Li exchange of 1-bromo-2-iodobenzene derivative 17 with BuLi and subsequent formylation at -40 °C of the highly reactive 2-bromophenyllithium intermediate using DMF, which is difficult to achieve by a conventional batch process due to the conversion of the highly reactive 2-bromophenyllithium intermediate into benzyne even at -78 °C. Late-stage cyclization to give the isoindolin-1-one ring system, through reductive amination of 18 followed by palladium-catalyzed carbonylation with carbon monoxide and intramolecular cyclization, efficiently afforded 1 for its further research and development.


Assuntos
Benzaldeídos/farmacologia , Colinérgicos/farmacologia , Receptor Muscarínico M1/metabolismo , Regulação Alostérica/efeitos dos fármacos , Benzaldeídos/síntese química , Benzaldeídos/química , Colinérgicos/síntese química , Colinérgicos/química , Humanos , Estrutura Molecular
3.
Arch Pharm Res ; 42(8): 722-731, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31350730

RESUMO

Isoorientin (ISO) is considered one of the most important flavonoids with various pharmacological effects such as antioxidant, anti-inflammatory, and anti-cancer activities. Despite these beneficial activities, the effects of ISO on learning and memory have not been investigated so far. The current study evaluated the memory-enhancing effects of ISO in a scopolamine-treated mouse model by using the Y-maze and passive avoidance tests. The results showed that ISO (5 and 10 mg/kg, p.o.) treatment significantly improved the cognitive impairments caused by scopolamine. Additionally, ISO significantly decreased scopolamine-induced acetylcholinesterase and thiobarbituric acid reactive substance activities in both the hippocampus and frontal cortex of mice. In addition, ISO significantly increased the levels of total superoxide dismutase induced by scopolamine in the hippocampus and frontal cortex. Moreover, Western blot results indicated that ISO reversed the decreases in expression of phosphorylated cAMP response element binding (CREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus and frontal cortex of scopolamine-treated mice. Thus, our results provide initial evidence that ISO ameliorates scopolamine-induced memory and cognitive impairments partly by restoring the cholinergic system, antioxidant defense, and p-CREB/BDNF signaling pathway, thereby exhibiting memory-enhancing activities.


Assuntos
Antioxidantes/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Colinérgicos/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Luteolina/farmacologia , Animais , Colinérgicos/química , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Luteolina/química , Masculino , Memória/efeitos dos fármacos , Camundongos , Estrutura Molecular , Escopolamina , Transdução de Sinais/efeitos dos fármacos
4.
Molecules ; 24(2)2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30669383

RESUMO

Hwangryunhaedok-tang (HRT) is a traditional oriental herbal formula used in Asian countries for treating inflammatory diseases and controlling fever. Our present study aimed to determine whether HRT has therapeutic effects for patients with vascular dementia (VaD) using a bilateral common carotid artery occlusion (BCCAO) rat model and assessing spatial memory impairment and activation of neuroinflammation. BCCAO was performed in male Sprague Dawley rats to induce VaD, and oral HRT was administered daily for 30 d. Our data showed that HRT ameliorated BCCAO-induced memory and cognitive impairment in behavioral tests. In addition, HRT reversed cholinergic dysfunction and neuronal damage in the hippocampus of BCCAO rats. Furthermore, HRT attenuated microglial activation and reduced the phosphorylation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase (JNK) induced by BCCAO. Simultaneous high-performance liquid chromatography analysis of HRT using index compounds from the herbal composition revealed that both HRT ethanol extract and commercial HRT granules primarily comprise geniposide, baicalin, and berberine. Our study showed that HRT administration resulted in the prevention of neuronal injury induced by BCCAO through improvement of cholinergic dysfunction and inhibition of neuroinflammatory responses, suggesting that HRT may have potential as a treatment for VaD.


Assuntos
Demência Vascular/metabolismo , Demência Vascular/psicologia , Memória/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Acetilcolina/metabolismo , Animais , Colinérgicos/química , Colinérgicos/farmacologia , Cromatografia Líquida de Alta Pressão , Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/tratamento farmacológico , Demência Vascular/fisiopatologia , Modelos Animais de Doenças , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Estrutura Molecular , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Extratos Vegetais/química , Ratos
5.
Eur J Med Chem ; 157: 161-176, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30096650

RESUMO

The multifactorial nature of Alzheimer's disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A novel family of donepezil-butylated hydroxytoluene (BHT) hybrids were designed, synthesized and evaluated as multifunctional ligands against AD. The optimal compound 7d displayed a balanced multifunctional profile covering an intriguing acetylcholinesterase (AChE) inhibition (IC50, 0.075 µM for eeAChE and 0.75 µM for hAChE) and Monoamine oxidase B (MAO-B) inhibition (IC50, 7.4 µM for hMAO-B), excellent antioxidant activity (71.7 µM of IC50 by DPPH method, 0.82 and 1.62 trolox equivalent by ABTS method and ORAC method respectively), and inhibitory effects on self-induced, hAChE-induced Aß aggregation. Moreover, 7d possessed neuroprotective potency against H2O2-induced oxidative damage on PC12 cells and Lipopolysaccharides (LPS)-stimulated inflammation on BV2 cells. Compound 7d was capable of penetrating BBB and presented good liver microsomal metabolic stability. Importantly, compound 7d could dose-dependently reverse scopolamine-induced memory deficit in mice without acute toxicity. Taken together, those outstanding results highlight the donepezil-BHT hybrid 7d as a promising prototype in the research of innovative compound for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Colinérgicos/farmacologia , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/química , Hidroxitolueno Butilado/química , Hidroxitolueno Butilado/farmacologia , Linhagem Celular , Colinérgicos/síntese química , Colinérgicos/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Donepezila , Relação Dose-Resposta a Droga , Indanos/química , Indanos/farmacologia , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Piperidinas/química , Piperidinas/farmacologia , Agregados Proteicos/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
6.
Mol Pharm ; 15(6): 2206-2223, 2018 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-29745222

RESUMO

In line with the modern multi-target-directed ligand paradigm of Alzheimer's disease (AD), a series of 19 compounds composed of flavone and cyanoacetamide groups have been synthesized and evaluated as multifunctional agents against AD. Biological evaluation demonstrated that compounds 7j, 7n, 7o, 7r, and 7s exhibited excellent inhibitory potency (AChE, IC50 of 0.271 ± 0.012 to 1.006 ± 0.075 µM) and good selectivity toward acetylcholinesterase, significant antioxidant activity, good modulation effects on self-induced Aß aggregation, low cytotoxicity, and neuroprotection in human neuroblastoma SK-N-SH cells. Further, an inclusive study on the interaction of 7j, 7n, 7o, 7r, and 7s with AChE at physiological pH 7.2 using fluorescence, circular dichroism, and molecular docking methods suggested that these derivatives bind strongly to the peripheral anionic site of AChE mostly through hydrophobic interactions. Overall, the multifunctional profiles and strong AChE binding affinity highlight these compounds as promising prototypes for further pursuit of innovative multifunctional drugs for AD.


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Desenho de Fármacos , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/química , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Linhagem Celular Tumoral , Colinérgicos/química , Colinérgicos/farmacologia , Colinérgicos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Ensaios Enzimáticos , Flavonas/química , Humanos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Nitrilos/química , Agregados Proteicos/efeitos dos fármacos , Ligação Proteica
7.
ACS Chem Neurosci ; 9(7): 1572-1581, 2018 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-29678111

RESUMO

The pharmacology of the M5 muscarinic acetylcholine receptor (mAChR) is the least understood of the five mAChR subtypes due to a historic lack of selective small molecule tools. To address this shortcoming, we have continued the optimization effort around the prototypical M5 positive allosteric modulator (PAM) ML380 and have discovered and optimized a new series of M5 PAMs based on a chiral N-(indanyl)piperidine amide core with robust SAR, human and rat M5 PAM EC50 values <100 nM and rat brain/plasma Kp values of ∼0.40. Interestingly, unlike M1 and M4 PAMs with unprecedented mAChR subtype selectivity, this series of M5 PAMs displayed varying degrees of PAM activity at the other two natively Gq-coupled mAChRs, M1 and M3, yet were inactive at M2 and M4.


Assuntos
Colinérgicos/farmacologia , Regulação Alostérica , Amidas/química , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Colinérgicos/síntese química , Colinérgicos/química , Colinérgicos/farmacocinética , Descoberta de Drogas , Humanos , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Piperidinas/química , Ratos Sprague-Dawley , Receptores Muscarínicos/metabolismo , Relação Estrutura-Atividade
8.
ACS Chem Neurosci ; 9(7): 1818-1828, 2018 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-29683647

RESUMO

Recent years have seen a large increase in the discovery of allosteric ligands targeting muscarinic acetylcholine receptors (mAChRs). One of the challenges in screening such compounds is to understand their mechanisms of action and define appropriate parameter estimates for affinity, cooperativity and efficacy. Herein we describe the mechanisms of action and structure-activity relationships for a series of "pan-Gq-coupled" muscarinic acetylcholine (ACh) receptor (mAChR) positive allosteric modulators (PAMs). Using a combination of radioligand binding, functional inositol phosphate accumulation assays, receptor alkylation and operational data analysis, we show that most compounds in the series derive their variable potency and selectivity from differential cooperativity at the M1, M3 and M5 mAChRs. None of the PAMs showed greater than 10-fold subtype selectivity for the agonist-free receptor, but VU6007705, VU6007678, and VU6008555 displayed markedly increased cooperativity compared to the parent molecule and M5 mAChR-preferring PAM, ML380 (αß > 100), in the presence of ACh. Most of the activity of these PAMs derives from their ability to potentiate ACh binding affinity at mAChRs, though VU6007678 was notable for also potentiating ACh signaling efficacy and robust allosteric agonist activity. These data provide key insights for the future design of more potent and subtype-selective mAChR PAMs.


Assuntos
Colinérgicos/farmacologia , Regulação Alostérica , Animais , Células CHO , Colinérgicos/química , Cricetulus , Indazóis/química , Indazóis/farmacologia , Estrutura Molecular , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Muscarínicos/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia
9.
Eur J Med Chem ; 139: 68-83, 2017 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-28800459

RESUMO

By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a novel series of cinnamamide-dibenzylamine hybrids have been designed, synthesized, and evaluated biologically. In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit ChEs, strong potency inhibitory of self-induced ß-amyloid (Aß) aggregation and to act as potential antioxidants and biometal chelators. A Lineweaver-Burk plot and molecular modeling study showed that compound 7f targeted both the CAS and PAS of AChE. In addition, compound 7f could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Overall, all of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7f as the lead structure worthy of further investigation.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Benzilaminas/farmacologia , Colinérgicos/farmacologia , Inibidores da Colinesterase/farmacologia , Cinamatos/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/química , Benzilaminas/química , Barreira Hematorretiniana/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Morte Celular/efeitos dos fármacos , Colinérgicos/síntese química , Colinérgicos/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cinamatos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Ratos , Relação Estrutura-Atividade
10.
Nat Commun ; 8(1): 189, 2017 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-28775269

RESUMO

Cholinergic neuromodulation in the hippocampus controls the salience of background context memory acquired in the presence of elemental stimuli predicting an aversive reinforcement. With pharmacogenetic inhibition we here demonstrate that hilar perforant path-associated (HIPP) cells of the dentate gyrus mediate the devaluation of background context memory during Pavlovian fear conditioning. The salience adjustment is sensitive to reduction of hilar neuropeptide Y (NPY) expression via dominant negative CREB expression in HIPP cells and to acute blockage of NPY-Y1 receptors in the dentate gyrus during conditioning. We show that NPY transmission and HIPP cell activity contribute to inhibitory effects of acetylcholine in the dentate gyrus and that M1 muscarinic receptors mediate the cholinergic activation of HIPP cells as well as their control of background context salience. Our data provide evidence for a peptidergic local circuit in the dentate gyrus that mediates the cholinergic encoding of background context salience during fear memory acquisition.Intra-hippocampal circuits are essential for associating a background context with behaviorally salient stimuli and involve cholinergic modulation at SST+ interneurons. Here the authors show that the salience of the background context memory is modulated through muscarinic activation of NPY+ hilar perforant path associated interneurons and NPY signaling in the dentate gyrus.


Assuntos
Condicionamento Psicológico , Giro Denteado/citologia , Memória , Neurônios/metabolismo , Neuropeptídeo Y/genética , Acetilcolina/química , Animais , Comportamento Animal , Colinérgicos/química , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Medo , Inativação Gênica , Genes Dominantes , Células HEK293 , Hipocampo/metabolismo , Hipocampo/fisiologia , Humanos , Interneurônios/metabolismo , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeo Y/fisiologia , Receptor Muscarínico M1/metabolismo , Receptores de Neuropeptídeo Y/metabolismo
11.
Nat Commun ; 8: 15683, 2017 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-28589928

RESUMO

The retina processes visual images to compute features such as the direction of image motion. Starburst amacrine cells (SACs), axonless feed-forward interneurons, are essential components of the retinal direction-selective circuitry. Recent work has highlighted that SAC-mediated dendro-dendritic inhibition controls the action potential output of direction-selective ganglion cells (DSGCs) by vetoing dendritic spike initiation. However, SACs co-release GABA and the excitatory neurotransmitter acetylcholine at dendritic sites. Here we use direct dendritic recordings to show that preferred direction light stimuli evoke SAC-mediated acetylcholine release, which powerfully controls the stimulus sensitivity, receptive field size and action potential output of ON-DSGCs by acting as an excitatory drive for the initiation of dendritic spikes. Consistent with this, paired recordings reveal that the activation of single ON-SACs drove dendritic spike generation, because of predominate cholinergic excitation received on the preferred side of ON-DSGCs. Thus, dendro-dendritic release of neurotransmitters from SACs bi-directionally gate dendritic spike initiation to control the directionally selective action potential output of retinal ganglion cells.


Assuntos
Acetilcolina/química , Potenciais de Ação , Dendritos/fisiologia , Células Ganglionares da Retina/citologia , Algoritmos , Células Amácrinas/citologia , Animais , Colinérgicos/química , Feminino , Masculino , Inibição Neural/fisiologia , Estimulação Luminosa , Fótons , Coelhos , Receptores Colinérgicos/metabolismo , Retina/metabolismo , Transdução de Sinais , Sinapses/fisiologia , Temperatura
12.
Biochem Biophys Res Commun ; 486(2): 391-397, 2017 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-28315331

RESUMO

As a frequently used neonicotinoid insecticide, imidacloprid can impair the chemoreceptive behavior of honey bees even at sublethal doses, while the physiochemical mechanism has not been further revealed. Here, multiple fluorescence spectra, thermodynamic method, and molecular docking were used to study the interaction and the functional inhibition of imidacloprid to the recombinant CSP1 protein in Asian honey bee, Apis cerana. The results showed that the fluorescence intensity (λem = 332 nm) of CSP1 could be significantly quenched by imidacloprid in a dynamic mode. During the quenching process, ΔH > 0, ΔS > 0, indicating that the acting forces of imidacloprid with CSP1 are mainly hydrophobic interactions. Synchronous fluorescence showed that the fluorescence of CSP1 was mainly derived from tryptophan, and the hydrophobicity of tryptophan decreased with the increase of imidacloprid concentration. Molecular docking predicted the optimal pose and the amino acid composition of the binding process. Circular dichroism (CD) spectra showed that imidacloprid reduced the α-helix of CSP1 and caused the extension of the CSP1 peptide chain. In addition, the binding of CSP1 to floral scent ß-ionone was inhibited by nearly 50% of the apparent association constant (KA) in the presence of 0.28-2.53 ng/bee of imidacloprid, and the inhibition rate of nearly 95% at 3.75 ng/bee of imidacloprid at sublethal dose level. This study initially revealed the molecular physiochemical mechanism that sublethal doses of neonicotinoid still interact and inhibit the physiological function of the honey bees' chemoreceptive system.


Assuntos
Colinérgicos/toxicidade , Imidazóis/toxicidade , Proteínas de Insetos/química , Inseticidas/toxicidade , Nitrocompostos/toxicidade , Norisoprenoides/química , Sequência de Aminoácidos , Animais , Abelhas/efeitos dos fármacos , Abelhas/fisiologia , Colinérgicos/química , Clonagem Molecular , Escherichia coli/genética , Escherichia coli/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Expressão Gênica , Imidazóis/química , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Inseticidas/química , Cinética , Simulação de Acoplamento Molecular , Neonicotinoides , Nitrocompostos/química , Norisoprenoides/antagonistas & inibidores , Domínios Proteicos , Estrutura Secundária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Espectrometria de Fluorescência , Termodinâmica , Triptofano/química , Triptofano/metabolismo , Tirosina/química , Tirosina/metabolismo
14.
Mediators Inflamm ; 2016: 3957958, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27647951

RESUMO

Inflammatory markers are increased systematically and locally (e.g., skeletal muscle) in stroke patients. Besides being associated with cardiovascular risk factors, proinflammatory cytokines seem to play a key role in muscle atrophy by regulating the pathways involved in this condition. As such, they may cause severe decrease in muscle strength and power, as well as impairment in cardiorespiratory fitness. On the other hand, physical exercise (PE) has been widely suggested as a powerful tool for treating stroke patients, since PE is able to regenerate, even if partially, physical and cognitive functions. However, the mechanisms underlying the beneficial effects of physical exercise in poststroke patients remain poorly understood. Thus, in this study we analyze the candidate mechanisms associated with muscle atrophy in stroke patients, as well as the modulatory effect of inflammation in this condition. Later, we suggest the two strongest anti-inflammatory candidate mechanisms, myokines and the cholinergic anti-inflammatory pathway, which may be activated by physical exercise and may contribute to a decrease in proinflammatory markers of poststroke patients.


Assuntos
Exercício Físico , Inflamação/patologia , Músculo Esquelético/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Animais , Anti-Inflamatórios/uso terapêutico , Colinérgicos/química , Humanos , Camundongos , Atrofia Muscular/patologia , Atrofia Muscular/fisiopatologia , Ratos , Fatores de Risco
15.
Future Med Chem ; 8(11): 1179-89, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27402297

RESUMO

BACKGROUND: For long time Alzheimer's disease has been attributed to a cholinergic deficit. More recently, it has been considered dependent on the accumulation of the amyloid beta peptide (Aß), which promotes neuronal loss and impairs neuronal function. Results/methodology: In the present study, using biophysical and biochemical experiments we tested the hypothesis that in addition to its role as a neurotransmitter, acetylcholine may exert its action as an anti-Alzheimer agent through a direct interaction with Aß. CONCLUSION: Our data provide evidence that acetylcholine favors the soluble peptide conformation and exerts a neuroprotective effect against the neuroinflammatory and toxic effects of Aß. The present paper paves the way toward the development of new polyfunctional anti-Alzheimer therapeutics capable of intervening on both the cholinergic transmission and the Aß aggregation.


Assuntos
Acetilcolina/metabolismo , Acetilcolina/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Colinérgicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Acetilcolina/química , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Colinérgicos/química , Colinérgicos/metabolismo , Dicroísmo Circular , Humanos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Agregados Proteicos/efeitos dos fármacos
16.
Bioorg Chem ; 65: 38-47, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26851737

RESUMO

In the present study, one-pot synthesis of 1H-tetrazole linked 1,2,5,6-tetrahydronicotinonitriles under solvent-free conditions have been carried out in the presence of tetra-n-butyl ammonium fluoride trihydrated (TBAF) as catalyst and solvent. Computational studies have been conducted to elaborate two plausible mechanistic pathways of this one-pot reaction. Moreover, the synthesized compounds were screened for cholinesterases (acetylcholinesterase and butyrylcholinesterase) inhibition which are consider to be major malefactors of Alzheimer's disease (AD) to find lead compounds for further research in AD therapy.


Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Colinérgicos/síntese química , Colinérgicos/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Nitrilos/síntese química , Nitrilos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Colinérgicos/química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Nitrilos/química , Teoria Quântica , Relação Estrutura-Atividade
17.
Curr Pharm Des ; 22(14): 2124-33, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26818859

RESUMO

BACKGROUND: Cognitive deficits are amongst the most socially debilitating and least effectively treated symptoms of schizophrenia. The cholinergic system is a promising target for the design of novel drugs that can more effectively treat these symptoms. METHODS: We review the literature supporting the dysfunction of the cholinergic system in schizophrenia, discuss the preclinical and clinical data showing that modulating the cholinergic system could improve the symptoms of schizophrenia and review the main pharmacological strategies being investigated to treat cholinergic dysfunction in schizophrenia. RESULTS: Post-mortem and neuroimaging studies suggest there are widespread reductions in cholinergic receptor signalling in the cortex as well as subcortical regions, such as the hippocampus and striatum, in individuals with schizophrenia. Potential cholinergic drug targets are being pursued to increase receptor function. These include inhibiting the activity of the enzyme acetylcholinesterase to increase synaptic acetylcholine levels, and increasing the nicotinic receptor and muscarinic receptor activity with agonists or positive allosteric modulators. CONCLUSION: Amongst the most promising drug targets for treating schizophrenia are the α7 nicotinic receptor and the CHRM1 and CHRM4 muscarinic receptors. The recent development of allosteric modulators that selectively target these receptors offers the potential to more effectively treat the symptoms of schizophrenia.


Assuntos
Colinérgicos/farmacologia , Esquizofrenia/tratamento farmacológico , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Animais , Colinérgicos/química , Humanos , Esquizofrenia/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
18.
Dokl Biochem Biophys ; 464: 294-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26518551
19.
Neuropharmacology ; 97: 75-85, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25998276

RESUMO

Acetylcholine activates nicotinic acetylcholine receptors (nAChRs) by binding at an extracellular orthosteric site. Previous studies have described several positive allosteric modulators (PAMs) that are selective for homomeric α7 nAChRs. These include type I PAMs, which exert little or no effect on the rate of receptor desensitisation, and type II PAMs, which cause a dramatic loss of agonist-induced desensitisation. Here we report evidence that transmembrane mutations in α7 nAChRs have diverse effects on receptor activation and desensitisation by allosteric ligands. It has been reported previously that the L247T mutation, located toward the middle of the second transmembrane domain (at the 9' position), confers reduced levels of desensitisation. In contrast, the M260L mutation, located higher up in the TM2 domain (at the 22' position), does not show any difference in desensitisation compared to wild-type receptors. We have found that in receptors containing the L247T mutation, both type I PAMs and type II PAMs are converted into non-desensitising agonists. In contrast, in receptors containing the M260L mutation, this effect is seen only with type II PAMs. These findings, indicating that the M260L mutation has a selective effect on type II PAMs, have been confirmed both with previously described PAMs and also with a series of novel α7-selective PAMs. The novel PAMs examined in this study have close chemical similarity but diverse pharmacological properties. For example, they include compounds displaying effects on receptor desensitisation that are typical of classical type I and type II PAMs but, in addition, they include compounds with intermediate properties.


Assuntos
Colinérgicos/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/genética , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Acetilcolina/farmacologia , Sítio Alostérico/genética , Sítio Alostérico/fisiologia , Animais , Colinérgicos/química , Células HEK293 , Humanos , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Camundongos , Estrutura Molecular , Mutação , Oócitos , Ensaio Radioligante , Ratos , Receptores 5-HT3 de Serotonina/metabolismo , Xenopus laevis
20.
Neuroscience ; 292: 13-21, 2015 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-25681522

RESUMO

Yerba-mate (Ilex paraguariensis St. Hil.) is the most used beverage in Latin America with approximately 426 thousand of tons consumed per year. Considering the broad use of this plant, we aimed to investigate the anxiety-like and stimulant activity of both the hydroethanolic (HE) and aqueous (AE) extracts from leaves of I. paraguariensis. Swiss mice were treated with I. paraguariensis HE or AE chronically or acutely, respectively, followed by evaluation in the elevated plus-maze (EPM; anxiety-like paradigm), open field (OF; locomotor activity) or the step-down avoidance task (memory assessment). Following behavioral protocols the brains were collected for evaluation of acetylcholinesterase (AChE) activity ex vivo. Chronic treatment with HE induced an anxiolytic-like effect and increased motor activity besides augmented AChE activity. Additionally, acute treatment with AE prevented the scopolamine-induced memory deficit in the step-down avoidance task. Overall, our results indicate the importance of the I. paraguariensis-induced CNS effects, since it is a widely used nutraceutical. We have reported anxiolytic, stimulant and neuroprotective effects for this plant species. These effects are potentially modulated by the cholinergic system as well as by caffeine.


Assuntos
Ansiolíticos/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Ilex paraguariensis , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta , Acetilcolinesterase/metabolismo , Animais , Ansiolíticos/química , Ansiedade/tratamento farmacológico , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Cafeína/química , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/química , Colinérgicos/química , Colinérgicos/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Ilex paraguariensis/química , Masculino , Transtornos da Memória/prevenção & controle , Camundongos , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/química , Fototerapia , Extratos Vegetais/química , Folhas de Planta/química , Escopolamina
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