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1.
Mini Rev Med Chem ; 19(15): 1219-1254, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31735158

RESUMO

Nowadays, heterocyclic compounds act as a scaffold and are the backbone of medicinal chemistry. Among all of the heterocyclic scaffolds, 1,4-Dihydropyridine (1,4-DHP) is one of the most important heterocyclic rings that possess prominent therapeutic effects in a very versatile manner and plays an important role in synthetic, medicinal, and bioorganic chemistry. The main aim of the study is to review and encompass relevant studies related to 1,4-DHP and excellent therapeutic benefits of its derivatives. An extensive review of Pubmed-Medline, Embase and Lancet's published articles was done to find all relevant studies on the activity of 1,4-DHP and its derivatives. 1,4-DHP is a potent Voltage-Gated Calcium Channel (VGCC) antagonist derivative which acts as an anti-hypertensive, anti- anginal, anti-tumor, anti-inflammatory, anti-tubercular, anti-cancer, anti-hyperplasia, anti-mutagenic, anti-dyslipidemic, and anti-ulcer agent. From the inferences of the study, it can be concluded that the basic nucleus, 1,4-DHP which is a voltage-gated calcium ion channel blocker, acts as a base for its derivatives that possess different important therapeutic effects. There is a need of further research of this basic nucleus as it is a multifunctional moiety, on which addition of different groups can yield a better drug for its other activities such as anti-convulsant, anti-oxidant, anti-mutagenic, and anti-microbial. This review would be significant for further researches in the development of several kinds of drugs by representing successful matrix for the medicinal agents.


Assuntos
Di-Hidropiridinas/farmacologia , Compostos Heterocíclicos/farmacologia , Neoplasias/tratamento farmacológico , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/química , Antiulcerosos/farmacologia , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/metabolismo , Di-Hidropiridinas/química , Compostos Heterocíclicos/química , Úlcera/tratamento farmacológico
2.
Pharm Res ; 36(9): 137, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332533

RESUMO

PURPOSE: Pitt Hopkins Syndrome (PTHS) is a rare genetic disorder caused by mutations of a specific gene, transcription factor 4 (TCF4), located on chromosome 18. PTHS results in individuals that have moderate to severe intellectual disability, with most exhibiting psychomotor delay. PTHS also exhibits features of autistic spectrum disorders, which are characterized by the impaired ability to communicate and socialize. PTHS is comorbid with a higher prevalence of epileptic seizures which can be present from birth or which commonly develop in childhood. Attenuated or absent TCF4 expression results in increased translation of peripheral ion channels Kv7.1 and Nav1.8 which triggers an increase in after-hyperpolarization and altered firing properties. METHODS: We now describe a high throughput screen (HTS) of 1280 approved drugs and machine learning models developed from this data. The ion channels were expressed in either CHO (KV7.1) or HEK293 (Nav1.8) cells and the HTS used either 86Rb+ efflux (KV7.1) or a FLIPR assay (Nav1.8). RESULTS: The HTS delivered 55 inhibitors of Kv7.1 (4.2% hit rate) and 93 inhibitors of Nav1.8 (7.2% hit rate) at a screening concentration of 10 µM. These datasets also enabled us to generate and validate Bayesian machine learning models for these ion channels. We also describe a structure activity relationship for several dihydropyridine compounds as inhibitors of Nav1.8. CONCLUSIONS: This work could lead to the potential repurposing of nicardipine or other dihydropyridine calcium channel antagonists as potential treatments for PTHS acting via Nav1.8, as there are currently no approved treatments for this rare disorder.


Assuntos
Di-Hidropiridinas/farmacologia , Reposicionamento de Medicamentos/métodos , Hiperventilação/tratamento farmacológico , Deficiência Intelectual/tratamento farmacológico , Canal de Potássio KCNQ1/antagonistas & inibidores , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Animais , Teorema de Bayes , Células CHO , Cricetulus , Di-Hidropiridinas/química , Facies , Células HEK293 , Humanos , Canal de Potássio KCNQ1/metabolismo , Aprendizado de Máquina , Bloqueadores dos Canais de Potássio/química , Bibliotecas de Moléculas Pequenas/química , Bloqueadores dos Canais de Sódio/química , Relação Estrutura-Atividade , Bloqueadores do Canal de Sódio Disparado por Voltagem/química
3.
Chem Biol Interact ; 306: 1-9, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30965050

RESUMO

The inhibitory effects of antihypertensive drugs (dihydropyridine calcium channel blockers, angiotensin II receptor blockers, and angiotensin-converting enzyme inhibitors) on cytochrome P450 2J2 (CYP2J2) activity were examined. Amlodipine, azelnidipine, barnidipine, benidipine, cilnidipine, efonidipine, felodipine, manidipine, nicardipine, nifedipine, nilvadipine, nisoldipine, nitrendipine, telmisartan, delapril, and quinapril inhibited luciferin-2J2/4F12 O-dealkylase activity of recombinant human CYP2J2 in a concentration-dependent manner (IC50 = 0.116-9.19 µM). Kinetic analyses of the inhibition indicated that azelnidipine, barnidipine, benidipine, cilnidipine, efonidipine, manidipine, nicardipine, telmisartan, delapril, and quinapril competitively inhibited CYP2J2 activity, while amlodipine, felodipine, nifedipine, nilvadipine, nisoldipine, and nitrendipine showed mixed inhibition. Among these drugs, manidipine showed the strongest reversible inhibition with Ki value of 0.0294 µM. The docking simulation data supported the potent inhibition of CYP2J2 by these drugs. Next, the effect of preincubation on CYP2J2 inhibition was investigated to determine whether these antihypertensive drugs inhibited CYP2J2 activity in a metabolism-dependent manner. A 20-min preincubation of azelnidipine and felodipine in the presence of NADPH potentiated the inhibition of CYP2J2. Furthermore, kinetic analysis of the inactivation showed that azelnidipine caused a preincubation time- and concentration-dependent decrease in CYP2J2 activity yielding kinact/KI value of 105 l/mmol/min, although felodipine showed no preincubation time-dependent inhibition. The azelnidipine-mediated inactivation required NADPH. These results indicated that manidipine is a potent competitive reversible inhibitor while azelnidipine is a potent mechanism-based inactivator of human CYP2J2.


Assuntos
Anti-Hipertensivos/farmacologia , Ácido Azetidinocarboxílico/análogos & derivados , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Di-Hidropiridinas/farmacologia , Animais , Anti-Hipertensivos/química , Ácido Azetidinocarboxílico/química , Ácido Azetidinocarboxílico/farmacologia , Inibidores das Enzimas do Citocromo P-450/química , Di-Hidropiridinas/química , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
4.
Life Sci ; 227: 74-81, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31002920

RESUMO

AIMS: Benidipine is a dihydropyridine (DHP) derived Ca2+ antagonist, can block triple Ca2+ channels (L, N, and T). It has been used as a safety anti-hypertensive drug because of its long-acting relaxant effect on vascular smooth muscle (VSM). However, whether benidipine has similar pharmacological actions in airway smooth muscle (ASM) is unknown. This research aims to reveal the relaxant property and Ca2+ antagonistic effect of benidipine on ASM. MAIN METHODS: The relaxant property of mouse ASM was investigated by tissue tension tests, and Ca2+ antagonistic effect was evaluated through patch-clamp techniques. KEY FINDINGS: Benidipine caused dose-dependent relaxations on high K+ (80 mM) induced precontraction in mouse ASM, which relied on inhibition of extracellular Ca2+ influx, and 1 µM benidipine totally blocked L-type voltage-dependent Ca2+ channels (LVDCCs) currents in airway smooth muscle cells (ASMCs). Benidipine also showed dose-dependent inhibition of ACh-induced precontraction with or without the LVDCCs blocker nifedipine, and 100 µM benidipine blocked ACh-stimulated Ca2+ influx through not only LVDCCs but also non-selective cation channels (NSCCs). SIGNIFICANCE: Benidipine blocked LVDCCs and NSCCs to abolish these channels-mediated Ca2+ influx, which relaxed precontracted ASM. This study represented benidipine with a new potential medicinal value for ASM hypercontractility.


Assuntos
Di-Hidropiridinas/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Animais , Anti-Hipertensivos/farmacologia , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Di-Hidropiridinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Técnicas de Patch-Clamp , Sistema Respiratório/efeitos dos fármacos
5.
Bioelectrochemistry ; 127: 12-20, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30623791

RESUMO

This study presents evaluation of the possible interaction mechanism between calf thymus dsDNA and three calcium antagonists; nifedipine, lercanidipine and amlodipine. The interactions between Nifedipine-dsDNA and Lercanidipine-dsDNA were investigated by differential pulse voltammetry using two different interaction methods; at the dsDNA-electrochemical biosensor surface and in bulk incubated solution. Amlodipine was used as model drug in bulk incubated solution. The decrease in the peak current of guanine and adenine were used as an indicator for confirmation of the interaction event in acetate buffer of pH 4.70. In bulk incubated solution, after interaction with Nifedipine and Amlodipine the guanine signal was almost disappeared. At the dsDNA modified glassy carbon electrode surface, the peak currents of guanine and adenine were decreased while Nifedipine and Lercanidipine interacts with DNA. The interactions between Nifedipine-dsDNA and Lercanidipine-dsDNA were further studied by UV-Vis absorption spectroscopy which indicates the intermolecular interaction between these drugs and ds-DNA can be mainly through hydrogen bonding and van der Waals forces. Molecular docking calculations shown that the AMP-1-2, NDP and LDP-1-2-ctDNA having groove binding. Beside spectral data, docking studies elicited that AMP-1-2, NDP and LDP-1-2 complexes have different interaction and conformation trends to target (ctDNA).


Assuntos
Bloqueadores dos Canais de Cálcio/metabolismo , DNA/metabolismo , Di-Hidropiridinas/metabolismo , Substâncias Intercalantes/metabolismo , Nifedipino/metabolismo , Animais , Sítios de Ligação/efeitos dos fármacos , Técnicas Biossensoriais , Bloqueadores dos Canais de Cálcio/farmacologia , Bovinos , DNA/química , Di-Hidropiridinas/farmacologia , Técnicas Eletroquímicas , Substâncias Intercalantes/farmacologia , Simulação de Acoplamento Molecular , Nifedipino/farmacologia , Conformação de Ácido Nucleico/efeitos dos fármacos
6.
Biomed Pharmacother ; 109: 1532-1540, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551405

RESUMO

Nifedipine is a calcium channel blocker dihydropyridine that has been used in the treatment of hypertension. The production of reactive species and calcium overload are the main contributors to myocardial ischemia-reperfusion (I / R) injury. We investigated the ability of novel dihydropyridines (DHPs) to improve the effect of protecting against the injury induced by ischemia and reperfusion in cardioblasts when compared to nifedipine. Forty three DHPs were created varying the fatty chains derived from palmitic acid, stearic acid and oleic acids and aromatic moiety in addition to the addition of chemical elements such as chlorine, nitrogen dioxide, furfural, hydroxyl and methoxy. Cytotoxicity and inhibition of linoleic oxidation were evaluated for all new DHPs and also for nifedipine. The alpha-tocopherol and butylated hydroxytoluene (BHT) were used as antioxidants controls. The compounds with the best antioxidant potential were used in the ischemia and reperfusion (I / R) induction test in cardioblasts (H9c2). Cardioblasts were treated 24 h after assembly of plates and submitted to the ischemia simulation (30 min), after which, normoxia and cellular nutrition conditions were reestablished, simulating reperfusion (additional 30 min). Right after, cell viability, apoptosis, necrosis, and the generation of reactive oxygen species (ROS) were evaluated. Cell viability during I / R was not altered in cells treated with nifedipine, BHT and the new DHP composed of palmitic acid with hydroxyl group in the aromatic substituent. The other new DHPs increased cell viability during I / R simulation and reduced levels of reactive species compared to the I / R group, demonstrating the antioxidant capacity of the new DHPs. Therefore, DHPS with palmitic and oleic acids in the C3 and C5 position with NO2 or Cl in aromatic moiety, presented the highest antioxidant potential (linoleic oxidant test). The new DHPs increased cell viability during I / R simulation and reduced levels of reactive species compared to the ischemia and reperfusion group, demonstrating the antioxidant capacity of the new DHPs. Taken together, these results indicate that those new DHPs have a greater cardioprotective antioxidant capacity to face the damages of ischemia and reperfusion.


Assuntos
Cardiotônicos/farmacologia , Di-Hidropiridinas/farmacologia , Mioblastos/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Mioblastos/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Necrose/tratamento farmacológico , Necrose/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo
7.
J Virol ; 92(16)2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29899092

RESUMO

Lassa virus (LASV) belongs to the Mammarenavirus genus (family Arenaviridae) and causes severe hemorrhagic fever in humans. At present, there are no Food and Drug Administration (FDA)-approved drugs or vaccines specific for LASV. Here, high-throughput screening of an FDA-approved drug library was performed against LASV entry by using pseudotype virus bearing LASV envelope glycoprotein (GPC). Two hit compounds, lacidipine and phenothrin, were identified as LASV entry inhibitors in the micromolar range. A mechanistic study revealed that both compounds inhibited LASV entry by blocking low-pH-induced membrane fusion. Accordingly, lacidipine showed virucidal effects on the pseudotype virus of LASV. Adaptive mutant analyses demonstrated that replacement of T40, located in the ectodomain of the stable-signal peptide (SSP), with lysine (K) conferred LASV resistance to lacidipine. Furthermore, lacidipine showed antiviral activity against LASV, the closely related Mopeia virus (MOPV), and the New World arenavirus Guanarito virus (GTOV). Drug-resistant variants indicated that V36M in the ectodomain of the SSP mutant and V436A in the transmembrane domain of the GP2 mutant conferred GTOV resistance to lacidipine, suggesting the interface between SSP and GP2 is the target of lacidipine. This study shows that lacidipine is a candidate for LASV therapy, reinforcing the notion that the SSP-GP2 interface provides an entry-targeted platform for arenavirus inhibitor design.IMPORTANCE Currently, there is no approved therapy to treat Lassa fever; therefore, repurposing of approved drugs will accelerate the development of a therapeutic stratagem. In this study, we screened an FDA-approved library of drugs and identified two compounds, lacidipine and phenothrin, which inhibited Lassa virus entry by blocking low-pH-induced membrane fusion. Additionally, both compounds extended their inhibition against the entry of Guanarito virus, and the viral targets were identified as the SSP-GP2 interface.


Assuntos
Antivirais/farmacologia , Di-Hidropiridinas/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Vírus Lassa/efeitos dos fármacos , Piretrinas/farmacologia , Internalização do Vírus/efeitos dos fármacos , Arenaviridae/efeitos dos fármacos , Arenavirus do Novo Mundo/efeitos dos fármacos , Análise Mutacional de DNA , Farmacorresistência Viral , Vírus Lassa/fisiologia
8.
J Pharmacol Sci ; 137(1): 98-100, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29709270

RESUMO

We compared dilator actions of representative four Ca2+ channel blockers on the isolated lower esophagus sphincter (LES) and thoracic aorta from rats. Verapamil, diltiazem, nifedipine and cilnidipine suppressed KCl-induced contractions of LES and thoracic aorta in a concentration-dependent manner. The order of selectivity for LES, which was calculated as ratio of IC50 value for thoracic aorta divided by that for LES, was diltiazem > verapamil > nifedipine > cilnidipine. These results suggest that diltiazem more preferentially dilates the LES whereas cilnidipine is expected to have lower potential risk of gastroesophageal dysfunction during the antihypertensive therapy.


Assuntos
Aorta/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Di-Hidropiridinas/farmacologia , Diltiazem/farmacologia , Esfíncter Esofágico Inferior/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Nifedipino/farmacologia , Verapamil/farmacologia , Animais , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacologia , Bloqueadores dos Canais de Cálcio/efeitos adversos , Di-Hidropiridinas/efeitos adversos , Diltiazem/efeitos adversos , Relação Dose-Resposta a Droga , Refluxo Gastroesofágico/induzido quimicamente , Técnicas In Vitro , Masculino , Nifedipino/efeitos adversos , Cloreto de Potássio/farmacologia , Ratos Wistar , Verapamil/efeitos adversos
9.
Phytomedicine ; 43: 92-102, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29747759

RESUMO

BACKGROUND: Hypertension is a serious component of metabolic syndrome (MetS). HYPOTHESIS: This research investigates the potential protective effect of limonin against MetS-associated hypertension in comparison with azelnidipine, a common calcium channel blocker. STUDY DESIGN: MetS was induced in rats by 10% fructose in water and 3% salt in diet over a 16-week period. Limonin (50 mg/kg) and azelnidipine (5 mg/kg) were administered daily in the last four weeks METHODS: Non-invasive blood pressure (BP) was recorded in conscious animals. Concentration-response curves for phenylephrine (PE) and acetylcholine (ACh) were analysed in thoracic aorta (macrovessels) and kidney microvessels. Blood glucose level, serum insulin level, advanced glycation end products (AGEs), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA) and transforming growth factor-ß1 (TGF-ß1) were determined. RESULTS: Limonin alleviated elevations in systolic and diastolic BP associated with MetS similar to levels associated with azelnidipine. Limonin prevented the MetS induced exaggerated macro- and micro-vascular contractility to PE and the impaired dilatation to ACh. However, in vitro incubation with limonin partially alleviated the deteriorated vascular reactivity of aorta isolated from MetS animals or AGEs injured aorta. Limonin did not have direct relaxant effect on the isolated vessel. On the other hand, limonin reduced the elevated serum levels of AGEs, TNF-α and MDA. Limonin suppressed the vascular fibrosis through reducing the elevated serum level of TGF-ß1 and excessive aortic collagen deposition. Limonin decreased the elevated HOMA-IR in MetS animals. CONCLUSION: Limonin offsets the hypertensive and vascular impairment associated with MetS via attenuation of inflammation and fibrosis. Its impact is comparable to that of azelnidipine.


Assuntos
Ácido Azetidinocarboxílico/análogos & derivados , Di-Hidropiridinas/farmacologia , Hipertensão/prevenção & controle , Limoninas/farmacologia , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/fisiopatologia , Animais , Aorta Torácica/efeitos dos fármacos , Ácido Azetidinocarboxílico/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Frutose/efeitos adversos , Produtos Finais de Glicação Avançada/metabolismo , Hipertensão/etiologia , Resistência à Insulina/fisiologia , Limoninas/administração & dosagem , Masculino , Síndrome Metabólica/complicações , Ratos
10.
Eur J Med Chem ; 155: 1-12, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29843108

RESUMO

Nifedipine and isradipine are prominent examples of calcium channel blockers with a 1,4-dihydropyridine (DHP) scaffold. Although successfully used in clinics since decades for the treatment of hypertension, the binding mechanism to their target, the L-type voltage-gated calcium channel Cav1.2, is still incompletely understood. Recently, novel DHP derivatives with a condensed ring system have been discovered that show distinct selectivity profiles to different calcium channel subtypes. This property renders this DHP class as a promising tool to achieve selectivity towards distinct calcium channel subtypes. In this study, we identified a common binding mode for prominent DHPs nifedipine and isradipine using docking and pharmacophore analysis that is also able to explain the structure-activity relationship of a small subseries of DHP derivatives with a condensed ring system. These findings were used to guide the synthesis of twenty-two novel DHPs. An extensive characterization using 1H NMR, 13C NMR, mass spectra and elemental analysis was followed by whole cell patch clamp assays for analyzing activity at Cav1.2 and Cav3.2. Two compounds were identified with significant activity against Cav1.2. Additionally, we identified four compounds active against Cav3.2 of which three were selective over Cav1.2. Novel binding modes were analyzed using docking and pharmacophore analysis as well as molecular dynamics simulations.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Tipo T/metabolismo , Di-Hidropiridinas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/química , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
11.
Nature ; 556(7702): 520-524, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29670288

RESUMO

Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor superfamily and have important roles in food intake, anxiety and cancer biology 1,2 . The NPY-Y receptor system has emerged as one of the most complex networks with three peptide ligands (NPY, peptide YY and pancreatic polypeptide) binding to four receptors in most mammals, namely the Y1, Y2, Y4 and Y5 receptors, with different affinity and selectivity 3 . NPY is the most powerful stimulant of food intake and this effect is primarily mediated by the Y1 receptor (Y1R) 4 . A number of peptides and small-molecule compounds have been characterized as Y1R antagonists and have shown clinical potential in the treatment of obesity 4 , tumour 1 and bone loss 5 . However, their clinical usage has been hampered by low potency and selectivity, poor brain penetration ability or lack of oral bioavailability 6 . Here we report crystal structures of the human Y1R bound to the two selective antagonists UR-MK299 and BMS-193885 at 2.7 and 3.0 Å resolution, respectively. The structures combined with mutagenesis studies reveal the binding modes of Y1R to several structurally diverse antagonists and the determinants of ligand selectivity. The Y1R structure and molecular docking of the endogenous agonist NPY, together with nuclear magnetic resonance, photo-crosslinking and functional studies, provide insights into the binding behaviour of the agonist and for the first time, to our knowledge, determine the interaction of its N terminus with the receptor. These insights into Y1R can enable structure-based drug discovery that targets NPY receptors.


Assuntos
Arginina/análogos & derivados , Di-Hidropiridinas/química , Di-Hidropiridinas/metabolismo , Ácidos Difenilacéticos/química , Ácidos Difenilacéticos/metabolismo , Neuropeptídeo Y/metabolismo , Compostos de Fenilureia/química , Compostos de Fenilureia/metabolismo , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Receptores de Neuropeptídeo Y/química , Arginina/química , Arginina/metabolismo , Arginina/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Di-Hidropiridinas/farmacologia , Ácidos Difenilacéticos/farmacologia , Humanos , Fosfatos de Inositol/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Mutação , Neuropeptídeo Y/química , Neuropeptídeo Y/farmacologia , Ressonância Magnética Nuclear Biomolecular , Compostos de Fenilureia/farmacologia , Ligação Proteica , Receptores de Neuropeptídeo Y/agonistas , Receptores de Neuropeptídeo Y/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato
12.
J Pharmacol Sci ; 136(4): 196-202, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29656005

RESUMO

The purpose of this study was to create novel urate under-excretion animal models using pyrazinamide and to evaluate whether dihydropyridine calcium channel blockers (CCBs) have uricosuric effects in vivo. Adult male ICR mice were treated with pyrazinamide, vehicle (dimethyl sulfoxide: DMSO), or tap water. Thirty minutes later, pyrazinamide-treated mice were given benzbromarone, losartan, nilvadipine, nitrendipine, nifedipine or azelnidipine. Six hours after the second administration, urine (by urinary bladder puncture) and plasma were collected to measure uric acid and creatinine levels, and fractional excretion of uric acid (FEUA) and creatinine clearance (Ccr) were calculated and evaluated. There was no significant difference in the levels of plasma uric acid, plasma creatinine, Ccr, urinary N-acetyl-ß-d-glucosaminidase (NAG) and urinary NAG-creatinine ratio between water, DMSO, and pyrazinamide-treated mice. But the FEUA of pyrazinamide-treated mice was significantly lower than water mice. The FEUA was significantly higher in mice taking the dihydropyridine CCBs (nilvadipine, nitrendipine, nifedipine, and high-dose azelnidipine) than in pyrazinamide-treated mice. There was no significant difference in Ccr. Thus, a novel animal model created with PZA administration was useful as a urate under-excretion animal model that was probably URAT1-mediated, and the uricosuric effects of dihydropyridine CCBs were confirmed in vivo.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Di-Hidropiridinas/farmacologia , Modelos Animais , Uricosúricos , Animais , Creatinina/sangue , Creatinina/urina , Proteínas de Ligação a DNA , Masculino , Camundongos Endogâmicos ICR , Transportadores de Ânions Orgânicos , Ácido Úrico/sangue , Ácido Úrico/urina
13.
Molecules ; 23(4)2018 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-29617279

RESUMO

The number of effective first-line antibiotics for the treatment of Mycobacterium tuberculosis infection is strongly limited to a few drugs. Due to emerging resistance against those drugs, second- and third-line antibiotics have been established in therapy with certain problems and also increasing mycobacterial resistance. An alternative to such novel drugs or combined therapeutic regimes which may reduce resistance development is finding enhancers of mycobacterial drug effectiveness, especially enhancers that counteract causative resistance mechanisms. Such enhancers may reduce the extracellular drug efflux mediated by bacterial efflux pumps and thus enhance the intracellular drug toxicity. We developed novel 1,4-dihydropyridines (DHPs) as potential efflux pump inhibitors with some determined P-gp affinities. The influence on the antituberculotic drug toxicity has been investigated for three prominent antituberculotic drugs. Exclusive and selective toxicity enhancing effects have been detected for isoniazid (INH) which could be related to certain substituent effects of the 1,4-DHPs. So, structure-dependent activities have been found. Thus, promising enhancers could be identified and a suggested efflux pump inhibition is discussed.


Assuntos
Antituberculosos/farmacologia , Isoniazida/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Isoniazida/química , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Relação Estrutura-Atividade
14.
Physiol Int ; 105(1): 53-60, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29602295

RESUMO

Moderate hypothermia (25-31 °C) may have a significant influence on vascular tone. At present, very little is known about the role of endothelial nitric oxide on the hypothermia-induced responses. In this study, we investigated the effect of hypothermia (to 28 °C) on the vasodilatation induced by verapamil, a phenylalkylamine calcium channel blocker (10-9-3 × 10-4 M) and dihydropyridines, amlodipine (10-9-3 × 10-4 M), and benidipine (10-9-10-3 M) on 5-hydroxytryptamine (5-HT or serotonin) precontracted calf cardiac veins. Furthermore, the role of nitric oxide in the hypothermia-induced responses was analyzed. Ring preparations of veins obtained from calf hearts were suspended in organ baths containing 15 ml of Krebs-Henseleit solution, maintained at 37 °C, and continuously gassed with 95% O2-5% CO2. After a resting period, verapamil, amlodipine, and benidipine were applied cumulatively on serotonin (10-6 M) precontracted calf cardiac vein rings and induced concentration-dependent relaxations. In another part of the study, the medium temperature was decreased to 28 °C after the preparations were contracted with 5-HT, then cumulative concentrations of verapamil, amlodipine, or benidipine were added. During hypothermia, the pIC50 value, but not the maximal response, to all blockers were significantly higher than at 37 °C. Hypothermia in the presence of NG-nitro-l-arginine methyl ester (L-NAME, 10-4 M) decreased the pIC50 and Emax values to verapamil, amlodipine, and benidipine. Only one blocker was tested in each preparation. These results suggest that nitric oxide may play a role in the hypothermia-induced changes in vasodilation caused by verapamil, amlodipine, and benidipine in calf cardiac vein, but further research is needed to explain the complete mechanism.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Temperatura Baixa , Vasos Coronários/efeitos dos fármacos , Hipotermia Induzida , Óxido Nítrico/metabolismo , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Anlodipino/farmacologia , Animais , Bovinos , Vasos Coronários/metabolismo , Vasos Coronários/fisiopatologia , Di-Hidropiridinas/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Técnicas In Vitro , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Verapamil/farmacologia
15.
Mol Pain ; 14: 1744806918765806, 2018 Jan-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29580153

RESUMO

Background Following peripheral nerve chronic constriction injury, the accumulation of the α2δ-1 auxiliary subunit of voltage-gated Ca2+ channels in primary afferent terminals contributes to the onset of neuropathic pain. Overexpression of α2δ-1 in Xenopus oocytes increases the opening properties of Cav1.2 L-type channels and allows Ca2+ influx at physiological membrane potentials. We therefore posited that L-type channels play a role in neurotransmitter release in the superficial dorsal horn in the chronic constriction injury model of neuropathic pain. Results Whole-cell recording from lamina II neurons from rats, subject to sciatic chronic constriction injury, showed that the L-type Ca2+ channel blocker, nitrendipine (2 µM) reduced the frequency of spontaneous excitatory postsynaptic currents. Nitrendipine had little or no effect on spontaneous excitatory postsynaptic current frequency in neurons from sham-operated animals. To determine whether α2δ-1 is involved in upregulating function of Cav1.2 L-type channels, we tested the effect of the α2δ-1 ligand, gabapentin (100 µM) on currents recorded from HEK293F cells expressing Cav1.2/ß4/α2δ-1 channels and found a significant decrease in peak amplitude with no effect on control Cav1.2/ß4/α2δ-3 expressing cells. In PC-12 cells, gabapentin also significantly reduced the endogenous dihydropyridine-sensitive calcium current. In lamina II, gabapentin reduced spontaneous excitatory postsynaptic current frequency in neurons from animals subject to chronic constriction injury but not in those from sham-operated animals. Intraperitoneal injection of 5 mg/kg nitrendipine increased paw withdrawal threshold in animals subject to chronic constriction injury. Conclusion We suggest that L-type channels show an increased contribution to synaptic transmission in lamina II dorsal horn following peripheral nerve injury. The effect of gabapentin on Cav1.2 via α2δ-1 may contribute to its anti-allodynic action.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/fisiopatologia , Subunidades Proteicas/metabolismo , Substância Gelatinosa/metabolismo , Transmissão Sináptica , Aminas/farmacologia , Animais , Bovinos , Constrição Patológica , Ácidos Cicloexanocarboxílicos/farmacologia , Di-Hidropiridinas/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Gabapentina , Células HEK293 , Humanos , Hiperalgesia/patologia , Hiperalgesia/fisiopatologia , Masculino , Nitrendipino/farmacologia , Células PC12 , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos , Xenopus , Ácido gama-Aminobutírico/farmacologia
16.
J Atheroscler Thromb ; 25(8): 690-697, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29398679

RESUMO

AIM: Recently, calcium channel blockers (CCBs) have been reported to reduce atherosclerosis with anti-inflammatory or antiatherosclerotic effects in vivo. It is well established that monocytes and macrophages play important roles in promoting atherosclerosis. However, the effects of CCBs on macrophage activation remain unclear. The aim of this study was to evaluate the effects of azelnidipine, a dihydropyridine L-type CCB, on the activation of macrophages and to clarify the mechanisms of the effects of CCBs on atherosclerosis. METHODS: THP-1 monocytes, a human leukemic cell line, were stimulated with 50 ng/mL of phorbol-12-myristate-13-acetate (PMA) 1 h after pretreatment with 10 µM azelnidipine or dimethyl sulfoxide (DMSO), and harvested. RESULTS: Azelnidipine blocked the expression of intercellular adhesion molecule-1 quantified by FACS analysis. The expression levels of Apo E and MMP9, which are markers of macrophage differentiation, were inhibited by azelnidipine as evaluated by quantitative RT-PCR. The level of LOX-1 mRNA, a scavenger receptor, was also reduced significantly by pretreatment with 10 µM azelnidipine. Azelnidipine also lowered the uptake of acetylated LDL. The expression of the L-type calcium channel Cav1.2 was 10-fold higher after 24 h of PMA stimulation. A knockdown of the CACNA1C gene, which encodes Cav1.2 protein in humans, with siRNA blocked the effect of reducing adhesion by azelnidipine, indicating that the effects of azelnidipine on macrophage differentiation were expressed through the CACNA1C gene. CONCLUSION: Our results suggest that azelnidipine has potent antiatherosclerotic properties by inhibition of macrophage activation through Cav1.2.


Assuntos
Ácido Azetidinocarboxílico/análogos & derivados , Canais de Cálcio Tipo L/metabolismo , Adesão Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Di-Hidropiridinas/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/citologia , Ácido Azetidinocarboxílico/farmacologia , Células Cultivadas , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo
17.
Recent Pat Anticancer Drug Discov ; 13(2): 255-264, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29468983

RESUMO

BACKGROUND: P-glycoprotein (P-gp) causes the efflux of cancer chemotherapy drugs from tumor cells, so its inhibition can be one target for designing and synthesis of new anticancer drugs. OBJECTIVE: In this study, new compounds of 1,4-dihydropyridine (DHP) were recommended as inhibitors of P-gp. METHODS: We synthesized new symmetrical DHP with 36% - 43% yield by the reaction of new reactants. In biological studies, these compounds have high lipophilicity, and thus low water solubility. Four reactants I with different reactivity was computed and compared using DFT study. The LUMO-map was differently distributed on each reactant. Amine intermediate underwent tautomerism as a transition state and it seems to play important role in reaction progress. Calculations were performed to select suitable reactants. RESULTS: Two different reactants I, including one polar group and a non-polar group, were used to produce asymmetric compounds with 49% - 60% yield. These asymmetric DHPs were more soluble than symmetric DHPs. In the final step, another selected symmetric product (by the elimination of chlorine atom) was synthesized in high yield (74%) by using DFT study. CONCLUSION: In this study, selected reactants by DFT calculation have increased the yield of reaction from 36% to 74% without any catalyst. The diversity of products is a noticeable topic. Racemic asymmetric compounds with R and S enantiomers have the potential for enantiomeric separation. Each of these enantiomers could have a different physiological effect.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Química Farmacêutica/métodos , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Humanos , Estereoisomerismo
18.
Eur J Med Chem ; 145: 165-190, 2018 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-29324339

RESUMO

As an extension of our previous work on donepezil-based "bio-oxidizable" prodrug approach, two new classes of N-benzylpyridinium donepezil analogues in tetralone B2 and acetophenone B3 series and a new set of indanone derivatives B1 were investigated along with the corresponding dihydropyridine prodrugs A1-3. A total of fifty one N-benzylpyridinium quaternary donepezil analogues B1-3 and twenty two prodrugs A1-3 were synthesized and evaluated for their inhibitory activities against hAChE and eqBuChE. While most prodrugs A1-3 were demonstrated to be inactive against AChE (IC50 > 10 µM), a large number of the corresponding N-benzylpyridinium salt B1-3 exhibited appealing three-to-one-digit nanomolar hAChE inhibitory activities and even reaching subnanomolar activity (IC50 = 0.36 nM). In addition, in silico docking studies were conducted for several compounds to explain the more relevant in vitro results. Lastly, the influence of the two stereogenic centers in prodrugs A was also evaluated, highlighting not only marked differences in residual AChE inhibitory activity of the four separated isomers of prodrug 23h (IC50 ranging from 173 nM to 10 µM) but also significant variations of the oxidation rate between two separated diastereoisomers of prodrug 24a. This work provides useful information in the search of a preclinical candidate to conduct further development of this attractive "bio-oxidizable" prodrug strategy.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Di-Hidropiridinas/farmacologia , Pró-Fármacos/farmacologia , Compostos de Piridínio/farmacologia , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Di-Hidropiridinas/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Compostos de Piridínio/síntese química , Compostos de Piridínio/química , Sais/síntese química , Sais/química , Sais/farmacologia , Relação Estrutura-Atividade
19.
Antiviral Res ; 150: 130-136, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29274844

RESUMO

Currently, there are no therapeutic alternatives to DNA polymerase inhibitors to treat human cytomegalovirus (HCMV) infections, a major threat for immunocompromised patients and pregnant women. Here, we explored the potential to repurpose manidipine dihydrochloride (MND), a calcium antagonist clinically approved to treat hypertension, as a new anti-HCMV agent. MND emerged in a previous drug repurposing screen to find early inhibitors of HCMV replication, and now we confirm that it inhibits in the low micromolar range the replication of different HCMV strains, including clinical isolates and viruses resistant to approved DNA polymerase inhibitors. The antiviral activity of MND is specific for HCMV over different both DNA and RNA viruses. Further experiments in HCMV-infected cells testing the effects of MND on viral DNA synthesis and viral proteins expression revealed that it halts the progression of the virus cycle prior to viral DNA replication and E genes expression, but after IE proteins expression. According to these results, we observed that the overall antiviral activity of MND involves a specific interference with the transactivating functions of the viral Immediate-Early 2 (IE-2) protein, an essential viral transcription factor required for the progression of HCMV replication. Given that the inhibitory concentration against HCMV is in the range of clinically relevant concentrations of MND in humans, and the mechanism of action differs from that of the other available therapeutics, this already approved drug is an attractive candidate for repurposing in alternative anti-HCMV therapeutic protocols.


Assuntos
Antivirais/farmacologia , Infecções por Citomegalovirus/virologia , Citomegalovirus/efeitos dos fármacos , Di-Hidropiridinas/farmacologia , Proteínas Imediatamente Precoces/antagonistas & inibidores , Transativadores/antagonistas & inibidores , Animais , Linhagem Celular , Infecções por Citomegalovirus/tratamento farmacológico , Cães , Relação Dose-Resposta a Droga , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Imediatamente Precoces/metabolismo , Regiões Promotoras Genéticas , Transativadores/metabolismo , Ativação Transcricional/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
20.
Eur J Pharmacol ; 819: 198-206, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29221949

RESUMO

This study aims to examine the effects of a new 1,4-dihydropyridine derivative, VdiE-2N, on cell signaling pathways and mitochondrial events in head and neck squamous cell carcinoma (HNSCC) cells, and on a mice model of xenograft tumor growth/cell proliferation. Four HNSCC cell lines (HN13, HN12, HN6, and CAL27), HEK293 cells (human embryonic kidney 293 cells), and human oral healthy mucosa fibroblasts (OHMF) were used for in vitro assessment of cell viability (resazurin assay) and invasion capacity (modified Boyden chamber assay), and mitochondrial membrane potential (JC-1 fluorescence assay), morphology (transmission electron microscopy), and number of mitochondria (MitoTracker® imaging). SET and pDRP1 proteins were analyzed by immunofluorescence, and proteins involved in cell death/survival pathways were analyzed by Western blotting. HN12 xenograft tumors were established in the flank of Balb/c nude mice, and their characteristics and sensitivity to VdiE-2N were determined by immunohistochemistry and histology. VdiE-2N decreased cell viability in HNSCC cells (IC50 = 9.56 and 22.45µM for HN13 and HN12 cells, respectively) more strongly than it decreased cell viability in OHMF and HEK293 cells (IC50 = 32.90 and > 50µM, respectively). In HN13 cells, VdiE-2N dissipated mitochondrial membrane potential and altered the mitochondria size, shape, and number in a concentration-dependent manner, as well as it induced apoptosis and reduced their invasion capacity. Treatment of mice bearing xenograft tumors with VdiE-2N significantly diminished proliferation of cancer cells. Therefore, VdiE-2N induces HNSCC cell death in vitro through mitochondria-mediated apoptotic pathways and dampens tumor growth in vivo, thus supporting a potential anti-cancer effect.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/patologia , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Neoplasias de Cabeça e Pescoço/patologia , Animais , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/irrigação sanguínea , Carcinoma de Células Escamosas/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes myc/genética , Neoplasias de Cabeça e Pescoço/irrigação sanguínea , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Tamanho Mitocondrial/efeitos dos fármacos , Invasividade Neoplásica , Neovascularização Patológica/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço , Ensaios Antitumorais Modelo de Xenoenxerto
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