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1.
Acta Pharmacol Sin ; 41(5): 629-637, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31911638

RESUMO

Geissoschizine methyl ether (GM) is an indole alkaloid isolated from Uncaria rhynchophyll (UR) that has been used for the treatment of epilepsy in traditional Chinese medicine. An early study in a glutamate-induced mouse seizure model demonstrated that GM was one of the active ingredients of UR. In this study, electrophysiological technique was used to explore the mechanism underlying the antiepileptic activity of GM. We first showed that GM (1-30 µmol/L) dose-dependently suppressed the spontaneous firing and prolonged the action potential duration in cultured mouse and rat hippocampal neurons. Given the pivotal roles of ion channels in regulating neuronal excitability, we then examined the effects of GM on both voltage-gated and ligand-gated channels in rat hippocampal neurons. We found that GM is an inhibitor of multiple neuronal channels: GM potently inhibited the voltage-gated sodium (NaV), calcium (CaV), and delayed rectifier potassium (IK) currents, and the ligand-gated nicotinic acetylcholine (nACh) currents with IC50 values in the range of 1.3-13.3 µmol/L. In contrast, GM had little effect on the voltage-gated transient outward potassium currents (IA) and four types of ligand-gated channels (γ-amino butyric acid (GABA), N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainite (AMPA/KA receptors)). The in vivo antiepileptic activity of GM was validated in two electricity-induced seizure models. In the maximal electroshock (MES)-induced mouse seizure model, oral administration of GM (50-100 mg/kg) dose-dependently suppressed generalized tonic-clonic seizures. In 6-Hz-induced mouse seizure model, oral administration of GM (100 mg/kg) reduced treatment-resistant seizures. Thus, we conclude that GM is a promising antiepileptic candidate that inhibits multiple neuronal channels.

2.
Acta Pharmacol Sin ; 41(3): 293-302, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31316182

RESUMO

Nav1.7 channels are mainly distributed in the peripheral nervous system. Blockade of Nav1.7 channels with small-molecule inhibitors in humans might provide pain relief without affecting the central nervous system. Based on the facts that many reported Nav1.7-selective inhibitors contain aryl sulfonamide fragments, as well as a tricyclic antidepressant, maprotiline, has been found to inhibit Nav1.7 channels, we designed and synthesized a series of compounds with ethanoanthracene and aryl sulfonamide moieties. Their inhibitory activity on sodium channels were detected with electrophysiological techniques. We found that compound 10o potently inhibited Nav1.7 channels stably expressed in HEK293 cells (IC50 = 0.64 ± 0.30 nmol/L) and displayed a high Nav1.7/Nav1.5 selectivity. In mouse small-sized dorsal root ganglion neurons, compound 10o (10, 100 nmol/L) dose-dependently decreased the sodium currents and dramatically suppressed depolarizing current-elicited neuronal discharge. Preliminary in vivo experiments showed that compound 10o possessed good analgesic activity: in a mouse visceral pain model, administration of compound 10o (30-100 mg/kg, i.p.) effectively and dose-dependently suppressed acetic acid-induced writhing.

3.
ACS Med Chem Lett ; 10(1): 27-33, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30655942

RESUMO

Recent research suggests that KCNQ isoforms, particularly the KCNQ4 and KCNQ5 subtypes expressed in smooth muscle cells, are involved in both establishing and maintaining resting membrane potentials and regulating smooth muscle contractility. Retigabine (RTG) is a first-in-class antiepileptic drug that potentiates neuronal KCNQ potassium channels, but poor subtype selectivity limits its further application as a pharmacological tool. In this study, we improved the subtype specificity of retigabine by altering the N-1/3 substituents and discovered several compounds that show better selectivity for KCNQ4 and KCNQ5 channels. Among these compounds, 10g is highly selective for KCNQ4 and KCNQ5 channels without potentiating KCNQ1 and KCNQ2 channels. These results are an advance in the exploration of small molecule modifiers that selectively activate different KCNQ isoforms. The developed compounds could also serve as new pharmacological tools for elucidating the function of KCNQ channels natively expressed in various tissues.

4.
Acta Pharmacol Sin ; 40(4): 451-459, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29991710

RESUMO

Lappaconitine (LA) has been widely used for postoperative and cancer pain control. LA exhibits excellent analgesic activity with a longer effective time than common local anesthetics such as tetracaine and bupivacaine. However, the mechanisms underlying the featured analgesic activity of LA remain largely unknown. Here, we report that LA is an inhibitor of voltage-gated sodium channel 1.7 (Nav1.7) stably expressed in human embryonic kidney (HEK293) cells. LA inhibited Nav1.7 in a voltage-dependent manner with an IC50 value (with 95% confidence limits) of 27.67 (15.68-39.66) µmol/L when the cell was clamped at -70 mV. In comparison with the quick and reversible inhibition of Nav1.7 by tetracaine and bupivacaine, the inhibitory effect of LA was rather slow and irreversible. It took more than 10 min to achieve steady-state inhibition when LA (300 µmol/L) was administered. Unlike tetracaine and bupivacaine, LA affected neither the voltage-dependent activation nor the inactivation of the channels. Five residues in domain III and domain IV have been reported to be critical for the effects of the two local anesthetics on Nav channels. But our mutant study revealed that only two residues (F1737, N1742) located in domain IV were necessary for the inhibitory activity of LA. The slow onset, irreversibility, and lack of influence on channel activation and inactivation accompanied with the different molecular determinants suggest that LA may inhibit Nav1.7 channels in a manner different from local anesthetics. These results may help to understand the featured analgesic activity of LA, thus benefiting its application in the clinic and future drug development.


Assuntos
Aconitina/análogos & derivados , Analgésicos não Entorpecentes/farmacologia , Canais de Sódio Disparados por Voltagem/metabolismo , Aconitina/administração & dosagem , Aconitina/química , Aconitina/farmacologia , Analgésicos não Entorpecentes/química , Células Cultivadas , Células HEK293 , Humanos , Estrutura Molecular , Isoformas de Proteínas/efeitos dos fármacos
5.
Mol Pharmacol ; 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30504241

RESUMO

Recent studies identified HN38 as a novel KCNQ2 channel inhibitor. However, to date no study has carefully examined HN38 in regards to its mechanism of action or determined whether it inhibits KCNQ2/3 channels. To address these questions, we used heterologous expression of human KCNQ2/3 channels in HEK293T cells. Consistent with previous reports, we found that HN38 almost completely blocked KCNQ2 channel activity. This inhibition was independent of the presence of the KCNQ1-5 auxiliary neuronal subunit beta-secretase 1 (BACE-1). Similar to its parent compound, retigabine, HN38 required the presence of KCNQ2 tryptophan W236 for inhibition. Surprisingly, we found that HN38 maximally inhibited KCNQ2/3 channels, as well as the KCNQ2/3-mediated M-current in CA1 pyramidal neurons, by approximately 40%. This incomplete block of KCNQ2/3 channels by HN38 appears to be partially due to the conformation of the KCNQ2/3 outer vestibule and in particular the outer turret lysine 259 of KCNQ3 channels. We conclude that the KCNQ3 outer vestibule conformation regulates the ability of blockers, like HN38 as well as XE991, to inhibit KCNQ2/3 channels, which should be considered for the design of new KCNQ2/3 channels compounds.

6.
Bioorg Med Chem Lett ; 28(10): 1943-1948, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29650291

RESUMO

A series of N-sulfonaminoethyloxime derivatives of dehydroabietic acid were synthesized and investigated for their antibacterial activity against Staphylococcus aureus Newman strain and multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108 and NRS-271). Most of the target compounds having chloro, bromo, trifluoromethyl phenyl moiety exhibited potent in vitro antistaphylococcal activity. The meta-CF3 phenyl derivative T23 showed the highest activity with MIC of 0.39-0.78 µg/mL against S. aureus Newman, while several analogues showed similar potent antibacterial activity with MIC values between 0.78 and 1.56 µg/mL against five multidrug-resistant S. aureus. The stability of T35 in plasma of SD rat and the cellular cytotoxicity were also evaluated.


Assuntos
/química , Antibacterianos/síntese química , Oximas/química , Animais , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Estabilidade de Medicamentos , Testes de Sensibilidade Microbiana , Oximas/metabolismo , Oximas/farmacologia , Ratos , Ratos Sprague-Dawley , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
7.
Acta Pharmacol Sin ; 39(4): 587-596, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29094728

RESUMO

The Nav1.7 channel represents a promising target for pain relief. In the recent decades, a number of Nav1.7 channel inhibitors have been developed. According to the effects on channel kinetics, these inhibitors could be divided into two major classes: reducing activation or enhancing inactivation. To date, however, only several inhibitors have moved forward into phase 2 clinical trials and most of them display a less than ideal analgesic efficacy, thus intensifying the controversy regarding if an ideal candidate should preferentially affect the activation or inactivation state. In the present study, we investigated the action mechanisms of a recently clinically confirmed inhibitor CNV1014802 using both electrophysiology and site-directed mutagenesis. We found that CNV1014802 inhibited Nav1.7 channels through stabilizing a nonconductive inactivated state. When the cells expressing Nav1.7 channels were hold at 70 mV or 120 mV, the half maximal inhibitory concentration (IC50) values (with 95% confidence limits) were 1.77 (1.20-2.33) and 71.66 (46.85-96.48) µmol/L, respectively. This drug caused dramatic hyperpolarizing shift of channel inactivation but did not affect activation. Moreover, CNV1014802 accelerated the onset of inactivation and delayed the recovery from inactivation. Notably, application of CNV1014802 (30 µmol/L) could rescue the Nav1.7 mutations expressed in CHO cells that cause paroxysmal extreme pain disorder (PEPD), thereby restoring the impaired inactivation to those of the wild-type channel. Our study demonstrates that CNV1014802 enhances the inactivation but does not reduce the activation of Nav1.7 channels, suggesting that identifying inhibitors that preferentially affect inactivation is a promising approach for developing drugs targeting Nav1.7.


Assuntos
Analgésicos/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Éteres Fenílicos/farmacologia , Prolina/análogos & derivados , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Animais , Células CHO , Cricetulus , Fenômenos Eletrofisiológicos , Células HEK293 , Humanos , Mutagênese Sítio-Dirigida , Mutação , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Prolina/farmacologia
8.
Eur J Med Chem ; 127: 917-927, 2017 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-27837995

RESUMO

A series of 7-N-acylaminoethyl/propyloxime derivatives of dehydroabietic acid were synthesized and investigated for their antibacterial activity against Staphylococcus aureus Newman strain and multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108 and NRS-271). Most of the target compounds having trifluoromethyl phenyl/benzyl, halogen-substituted thiophenyl, benzothiophenyl or pyrrolyl moiety exhibited potent in vitro antibacterial activity. Among which, compounds 4m, 4x and 7j showed high antibacterial activity with minimum inhibitory concentration (MIC) values of 1.25-3.13 µg/mL against five multidrug-resistant S. aureus.


Assuntos
/síntese química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Desenho de Fármacos , Staphylococcus aureus/efeitos dos fármacos , /química , Antibacterianos/química , Técnicas de Química Sintética , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Relação Estrutura-Atividade
9.
J Med Chem ; 59(13): 6329-43, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27309376

RESUMO

A novel series of sigma (σ) receptor ligands based on an alkoxyisoxazole scaffold has been designed and synthesized. Preliminary receptor binding assays identified highly potent (Ki < 1 nM) and selective σ1 ligands devoid of binding interactions with the monoamine transporters DAT, NET, and SERT. In particular, compound 53 was shown to possess significant antinociceptive activity in the mouse formalin-induced inflammation pain model when administered intraperitoneally at 40 and 80 mg/kg. Initial pharmacokinetics evaluation indicated an excellent brain exposure following oral dosing in mice, suggesting that further investigation into the use of alkoxyisoxazoles as σ1 ligands for antinociception is warranted. This study supports the notion that selective σ1 antagonism could be a useful strategy in the development of novel antipain therapy.


Assuntos
Analgésicos/farmacologia , Isoxazóis/farmacologia , Dor/tratamento farmacológico , Receptores sigma/antagonistas & inibidores , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Formaldeído , Injeções Intraperitoneais , Isoxazóis/administração & dosagem , Isoxazóis/química , Ligantes , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Dor/induzido quimicamente , Relação Estrutura-Atividade
10.
11.
Acta Pharmacol Sin ; 37(1): 105-10, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26725738

RESUMO

AIM: To establish an improved, high-throughput screening techniques for identifying novel KCNQ2 channel activators. METHODS: KCNQ2 channels were stably expressed in CHO cells (KCNQ2 cells). Thallium flux assay was used for primary screening, and 384-well automated patch-clamp IonWorks Barracuda was used for hit validation. Two validated activators were characterized using a conventional patch-clamp recording technique. RESULTS: From a collection of 80 000 compounds, the primary screening revealed a total of 565 compounds that potentiated the fluorescence signals in thallium flux assay by more than 150%. When the 565 hits were examined in IonWorks Barracuda, 38 compounds significantly enhanced the outward currents recorded in KCNQ2 cells, and were confirmed as KCNQ2 activators. In the conventional patch-clamp recordings, two validated activators ZG1732 and ZG2083 enhanced KCNQ2 currents with EC50 values of 1.04±0.18 µmol/L and 1.37±0.06 µmol/L, respectively. CONCLUSION: The combination of thallium flux assay and IonWorks Barracuda assay is an efficient high-throughput screening (HTS) route for discovering KCNQ2 activators.


Assuntos
Bases de Dados de Compostos Químicos , Canal de Potássio KCNQ2/metabolismo , Animais , Células CHO , Cricetulus , Fluorescência , Ensaios de Triagem em Larga Escala , Ativação do Canal Iônico , Técnicas de Patch-Clamp , Tálio/metabolismo
12.
J Nat Prod ; 79(1): 89-97, 2016 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-26716755

RESUMO

Nine new C21 steroidal glycosides, named cynawilfosides A-I (1-9), along with 12 known compounds were isolated from the roots of Cynanchum wilfordii. The structures of the new compounds were elucidated by spectroscopic analysis and chemical methods. The five major components, cynawilfoside A (1), cynauricoside A (11), wilfoside C1N (16), wilfoside K1N (17), and cyanoauriculoside G (18), exhibited significant protection activity in a maximal electroshock (MES)-induced mouse seizure model with ED50 values of 48.5, 95.3, 124.1, 72.3, and 88.1 mg/kg, respectively.


Assuntos
Anticonvulsivantes/isolamento & purificação , Anticonvulsivantes/farmacologia , Cynanchum/química , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Pregnanos/isolamento & purificação , Pregnanos/farmacologia , Animais , Anticonvulsivantes/química , Modelos Animais de Doenças , Glicosídeos/química , Camundongos , Estrutura Molecular , Raízes de Plantas/química , Pregnanos/química , Saponinas , Convulsões
13.
Sci China Life Sci ; 58(1): 39-47, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25480324

RESUMO

Canonical transient receptor potential 4 (TRPC4) forms non-selective cation channels that contribute to phospholipase C-dependent Ca(2+) entry into cells following stimulation of G protein coupled receptors and receptor tyrosine kinases. Moreover, the channels are regulated by pertussis toxin-sensitive Gi/o proteins, lipids, and various other signaling mechanisms. TRPC4-containing channels participate in the regulation of a variety of physiological functions, including excitability of both gastrointestinal smooth muscles and brain neurons. This review is to present recent advances in the understanding of physiology and development of small molecular modulators of TRPC4 channels.


Assuntos
Canais de Cátion TRPC/fisiologia , Animais , Humanos , Canais de Cátion TRPC/química
14.
Acta Pharmacol Sin ; 34(10): 1359-66, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23933653

RESUMO

AIM: Retigabine, an activator of KCNQ2-5 channels, is currently used to treat partial-onset seizures. The aim of this study was to explore the possibility that structure modification of retigabine could lead to novel inhibitors of KCNQ2 channels, which were valuable tools for KCNQ channel studies. METHODS: A series of retigabine derivatives was designed and synthesized. KCNQ2 channels were expressed in CHO cells. KCNQ2 currents were recorded using whole-cell voltage clamp technique. Test compound in extracellular solution was delivered to the recorded cell using an ALA 8 Channel Solution Exchange System. RESULTS: A total of 23 retigabine derivatives (HN31-HN410) were synthesized and tested electrophysiologically. Among the compounds, HN38 was the most potent inhibitor of KCNQ2 channels (its IC50 value=0.10 ± 0.05 µmol/L), and was 7-fold more potent than the classical KCNQ inhibitor XE991. Further analysis revealed that HN38 (3 µmol/L) had no detectable effect on channel activation, but accelerated deactivation at hyperpolarizing voltages. In contrast, XE991 (3 µmol/L) did not affect the kinetics of channel activation and deactivation. CONCLUSION: The retigabine derivative HN38 is a potent KCNQ2 inhibitor, which differs from XE991 in its influence on the channel kinetics. Our study provides a new strategy for the design and development of potent KCNQ2 channel inhibitors.


Assuntos
Anticonvulsivantes/farmacologia , Carbamatos/farmacologia , Canal de Potássio KCNQ2/antagonistas & inibidores , Fenilenodiaminas/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Animais , Antracenos/farmacologia , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Células CHO , Carbamatos/síntese química , Carbamatos/química , Cricetinae , Cricetulus , Desenho de Fármacos , Concentração Inibidora 50 , Técnicas de Patch-Clamp , Fenilenodiaminas/síntese química , Fenilenodiaminas/química , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/química , Relação Estrutura-Atividade
15.
Org Lett ; 14(17): 4438-41, 2012 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-22882011

RESUMO

Two new limonoids, chukrasone A (1) incorporating a highly rearranged A/B ring system and chukrasone B (2) possessing the first 16,19-dinor limonoid backbone with an extended C3 unit at C-15, were isolated from Chukrasia tabularis. Their structures were characterized on the basis of detailed spectroscopic analysis. Compounds 1 and 2 exhibited potential inhibition of the delayed rectifier (I(K)) K(+) current.


Assuntos
Canal de Potássio Kv1.2/antagonistas & inibidores , Limoninas/isolamento & purificação , Limoninas/farmacologia , Meliaceae/química , Bloqueadores dos Canais de Potássio/farmacologia , Limoninas/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Casca de Planta/química , Caules de Planta/química
16.
Acta Pharmacol Sin ; 33(6): 728-36, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22609836

RESUMO

AIM: This study was conducted to test the selectivity of DC031050 on cardiac and neuronal potassium channels. METHODS: Human ether-à-go-go related gene (hERG), KCNQ and Kv1.2 channels were expressed in CHO cells. The delayed rectifier potassium current (I(K)) was recorded from dissociated hippocampal pyramidal neurons of neonatal rats. Whole-cell voltage patch clamp was used to record the voltage-activated potassium currents. Drug-containing solution was delivered using a RSC-100 Rapid Solution Changer. RESULTS: Both DC031050 and dofetilide potently inhibited hERG currents with IC(50) values of 2.3 ± 1.0 and 17.9 ± 1.2 nmol/L, respectively. DC031050 inhibited the I(K) current with an IC(50) value of 2.7 ± 1.5 µmol/L, which was >1000 times the concentration required to inhibit hERG current. DC031050 at 3 µmol/L did not significantly affect the voltage-dependence of the steady activation, steady inactivation of I(K), or the rate of I(K) from inactivation. Intracellular application of DC031050 (5 µmol/L) was insufficient to inhibit I(K). DC031050 up to 10 µmol/L had no effects on KCNQ2 and Kv1.2 channel currents. CONCLUSION: DC031050 is a highly selective hERG potassium channel blocker with a substantial safety margin of activity over neuronal potassium channels, thus holds significant potential for therapeutic application as a class III antiarrhythmic agent.


Assuntos
Antiarrítmicos/farmacologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Canais de Potássio KCNQ/metabolismo , Canal de Potássio Kv1.2/metabolismo , Fenetilaminas/farmacologia , Células Piramidais/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Antiarrítmicos/química , Células CHO , Cricetinae , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/genética , Expressão Gênica , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Humanos , Canais de Potássio KCNQ/antagonistas & inibidores , Canais de Potássio KCNQ/genética , Canal de Potássio Kv1.2/antagonistas & inibidores , Canal de Potássio Kv1.2/genética , Técnicas de Patch-Clamp , Fenetilaminas/química , Potássio/metabolismo , Células Piramidais/metabolismo , Ratos , Ratos Sprague-Dawley , Sulfonamidas/química
17.
Org Biomol Chem ; 10(7): 1448-58, 2012 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-22215113

RESUMO

Eighteen new limonoids, chubularisins A-R (1-18), along with eleven known analogues, were isolated from the stem bark of Chukrasia tabularis. The structures of 1-18 were elucidated on the basis of spectroscopic data and chemical evidence. Compound 1 represented the first example of 8,9,12-orthoester of phragmalin limonoids. Interestingly, compounds 4, 8, and 22 exhibited potent and selective inhibition against the delayed rectifier (I(K)) K(+) current with IC(50) values of 0.61, 2.03, and 2.15 µM, respectively.


Assuntos
Canal de Potássio Kv1.2/antagonistas & inibidores , Limoninas/farmacologia , Casca de Planta/química , Canal de Potássio Kv1.2/química , Limoninas/química
18.
Acta Pharmacol Sin ; 32(6): 781-8, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21623390

RESUMO

Human ether-a-go-go related gene (hERG) potassium (K(+)) channels play a critical role in cardiac action potential repolarization. Mutations that reduce hERG conductance or surface expression may cause congenital long QT syndrome (LQTS). However, the channels can be inhibited by structurally diverse small molecules, resulting in an acquired form of LQTS. Consequently, small molecules that increase the hERG current may be of value for treatment for LQTS. So far, nine hERG activators have been reported. The aim of this review is to discuss recent advances concerning the identification and action mechanism of hERG activators.


Assuntos
Canais de Potássio Éter-A-Go-Go/metabolismo , Síndrome do QT Longo/metabolismo , Bibliotecas de Moléculas Pequenas , Animais , Sítios de Ligação , Canais de Potássio Éter-A-Go-Go/genética , Canais de Potássio Éter-A-Go-Go/fisiologia , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Síndrome do QT Longo/congênito , Síndrome do QT Longo/tratamento farmacológico , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico
19.
Acta Pharmacol Sin ; 29(4): 405-12, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18358085

RESUMO

AIM: N,No-[oxybis(2,1-ethanediyloxy-2,1-ethanediyl)]bis(4-methyl)- benzenesulfonamide (OMBSA) is a hit compound with potent voltage-gated K+ (Kv) channel-blocking activities that was found while searching the MDL Available Chemicals Directory with a virtual screening approach. In the present study, the blocking actions of OMBSA on Kv channels and relevant mechanisms were characterized. METHODS: Whole-cell voltage-clamp recording was made in acutely dissociated hippocampal CA1 pyramidal neurons of newborn rats. RESULTS: Superfusion of OMBSA reversibly inhibited both the delayed rectifier (I(K)) and fast transient K+ currents (I(A)) with IC50 values of 2.1+/-1.1 micromol/L and 27.8+/-1.5 micromol/L, respectively. The inhibition was voltage independent. OMBSA markedly accelerated the decay time course of IK, without a significant effect on that of I(A). OMBSA did not change the activation, steady-state inactivation of IK, and its recovery from inactivation, but the compound caused a significant hyperpolarizing shift of the voltage dependence of the steady-state inactivation of I(A) and slowed down its recovery from inactivation. Intracellular dialysis of OMBSA had no effect on both I(K) and I(A). CONCLUSION: The results demonstrate that OMBSA blocks both I(K) and I(A) through binding to the outer mouth of the channel pore, as predicted by the molecular docking model used in the virtual screening. In addition, the compound differentially moderates the inactivation kinetics of the K+ channels through allosteric mechanisms.


Assuntos
Derivados de Benzeno/farmacologia , Eletrofisiologia , Bloqueadores dos Canais de Potássio/farmacologia , Sulfonamidas/farmacologia , Animais , Animais Recém-Nascidos , Canais de Potássio de Retificação Tardia/antagonistas & inibidores , Canais de Potássio de Retificação Tardia/fisiologia , Hipocampo/citologia , Hipocampo/fisiologia , Concentração Inibidora 50 , Ativação do Canal Iônico/efeitos dos fármacos , Cinética , Estrutura Molecular , Peso Molecular , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio/química , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/fisiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Ratos , Ratos Sprague-Dawley , Sulfonamidas/química , Tetraetilamônio/farmacologia
20.
Org Lett ; 9(5): 903-6, 2007 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17263543

RESUMO

[structure: see text] Chlorahololides A(1) and B(2), two highly complex sesquiterpenoid dimers, were isolated from Chloranthus holostegius. Their structures and absolute configurations were established by NMR spectroscopy, X-ray crystallography, and CD. Chlorahololides A (1) and B (2) exhibited potent and selective inhibition on the delayed rectifier (IK) K+ current, with an IC50 of 10.9 and 18.6 microM, respectively.


Assuntos
Magnoliopsida/química , Bloqueadores dos Canais de Potássio/química , Sesquiterpenos/química , Dicroísmo Circular , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Magnoliopsida/metabolismo , Modelos Moleculares , Estrutura Molecular , Bloqueadores dos Canais de Potássio/isolamento & purificação , Bloqueadores dos Canais de Potássio/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/metabolismo , Sesquiterpenos/farmacologia , Estereoisomerismo
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