RESUMEN
Acrylamide (S)-6, a potent and efficacious KCNQ2 (Kv7.2) opener, demonstrated significant activity in two models of neuropathic pain and in the formalin test, suggesting that KCNQ2 openers may be useful in the treatment of neuropathic pain including diabetic neuropathy.
Asunto(s)
Acrilamidas/química , Acrilamidas/farmacología , Canal de Potasio KCNQ2/metabolismo , Neuralgia/tratamiento farmacológico , Acrilamidas/síntesis química , Animales , Canal de Potasio KCNQ2/química , Masculino , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-DawleyRESUMEN
A hallmark of Alzheimer's disease (AD) pathology is the accumulation of brain amyloid ß-peptide (Aß), generated by γ-secretase-mediated cleavage of the amyloid precursor protein (APP). Therefore, γ-secretase inhibitors (GSIs) may lower brain Aß and offer a potential new approach to treat AD. As γ-secretase also cleaves Notch proteins, GSIs can have undesirable effects due to interference with Notch signaling. Avagacestat (BMS-708163) is a GSI developed for selective inhibition of APP over Notch cleavage. Avagacestat inhibition of APP and Notch cleavage was evaluated in cell culture by measuring levels of Aß and human Notch proteins. In rats, dogs, and humans, selectivity was evaluated by measuring plasma blood concentrations in relation to effects on cerebrospinal fluid (CSF) Aß levels and Notch-related toxicities. Measurements of Notch-related toxicity included goblet cell metaplasia in the gut, marginal-zone depletion in the spleen, reductions in B cells, and changes in expression of the Notch-regulated hairy and enhancer of split homolog-1 from blood cells. In rats and dogs, acute administration of avagacestat robustly reduced CSF Aß40 and Aß42 levels similarly. Chronic administration in rats and dogs, and 28-day, single- and multiple-ascending-dose administration in healthy human subjects caused similar exposure-dependent reductions in CSF Aß40. Consistent with the 137-fold selectivity measured in cell culture, we identified doses of avagacestat that reduce CSF Aß levels without causing Notch-related toxicities. Our results demonstrate the selectivity of avagacestat for APP over Notch cleavage, supporting further evaluation of avagacestat for AD therapy.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Precursor de Proteína beta-Amiloide/antagonistas & inhibidores , Oxadiazoles/farmacología , Sulfonamidas/farmacología , Adolescente , Adulto , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Células Cultivadas , Perros , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ratas , Ratas Sprague-Dawley , Receptores Notch/metabolismo , Transducción de Señal/efectos de los fármacos , Adulto JovenRESUMEN
During the course of our research efforts to develop a potent and selective γ-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-ß precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of γ-secretase (Aß40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced Aß40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.
RESUMEN
Compound 8a (BMS-191011), an opener of the cloned large-conductance, Ca2+-activated potassium (maxi-K) channel, demonstrated efficacy in in vivo stroke models, which led to its nomination as a candidate for clinical evaluation. Its maxi-K channel opening properties were consistent with its structural topology, being derived by combining elements from other known maxi-K openers. However, 8a suffered from poor aqueous solubility, which complicated elucidation of SAR during in vitro evaluation. The activity of 8a in in vivo stroke models and studies directed toward improving its solubility are reported herein. Enhanced solubility was achieved by appending heterocycles to the 8a scaffold, and a notable observation was made that inclusion of a simple amino group (anilines 8k and 8l) yielded excellent in vitro maxi-K ion channel opening activity and enhanced brain-to-plasma partitioning compared to the appended heterocycles.
Asunto(s)
Canales de Potasio de Gran Conductancia Activados por el Calcio/fisiología , Oxadiazoles/farmacología , Animales , Encéfalo/metabolismo , Cristalografía por Rayos X , Femenino , Técnicas In Vitro , Activación del Canal Iónico , Estructura Molecular , Oocitos/efectos de los fármacos , Oocitos/fisiología , Oxadiazoles/química , Oxadiazoles/farmacocinética , Técnicas de Placa-Clamp , Plasma , Ratas , Ratas Endogámicas SHR , Solubilidad , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/patología , Relación Estructura-Actividad , Xenopus laevisRESUMEN
The synthesis of a series of 3-beta-hydroxyethyl-4-arylquinolin-2-ones is described. These compounds contain hydrophilic and hydrophobic substituents ortho to the phenolic OH in the C ring of the quinolinone. Electrophysiological evaluation of the panel of compounds revealed that 11 and 16 with an unbranched ortho substituent retain activity as maxi-K ion channel openers. Members of this series of compounds can exist as stable atropisomers. Calculated estimates of the energy barrier for rotation around the aryl-aryl single bond in 3 is 31 kcal/mol. The atropisomers of (+/-)-3, (+/-)-4, and (+/-)-11 were separated by chiral HPLC and tested for their effect on maxi-K mediated outward current in hSlo injected X. laevis oocytes. The (-) isomer in each case was found to be more active than the corresponding (+) isomer, suggesting that the ion channel exhibits stereoselective activation. X-ray crystallographic structures of (+)-3 and (+)-11 were determined. Evaluation of the stability of (-)-3 at 80 degrees C in n-butanol indicated a 19.6% conversion to (+)-3 over 72 h. In human serum at 37 degrees C (-)-3 did not racemize over the course of the 30 h study.
Asunto(s)
Canales de Potasio de Gran Conductancia Activados por el Calcio/efectos de los fármacos , Quinolinas/síntesis química , Animales , Cristalografía por Rayos X , Femenino , Humanos , Técnicas In Vitro , Activación del Canal Iónico , Canales de Potasio de Gran Conductancia Activados por el Calcio/fisiología , Estructura Molecular , Oocitos/efectos de los fármacos , Oocitos/fisiología , Técnicas de Placa-Clamp , Quinolinas/química , Quinolinas/farmacología , Estereoisomerismo , Termodinámica , Xenopus laevisRESUMEN
Quinolinone 1 is a potent maxi-K potassium channel opener. In an effort to design analogs of 1 with a better inhibitory profile toward the CYP2C9 isozyme, the two acidic sites were chemically modified independently to generate a number of analogs. These analogs were evaluated as maxi-K channel openers in vitro using Xenopus laevis oocytes expressing cloned hSlo maxi-K channels. Compounds 15, 17, and 19 showed potent activity as maxi-K channel openers and were further evaluated for inhibition of the activity of the CYP2C9 isozyme. Compounds 17 and 19 showed diminished inhibitory potency against 2C9 and also against a panel of other more common CYP isozymes.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/antagonistas & inhibidores , Quinolonas/síntesis química , Animales , Sitios de Unión , Citocromo P-450 CYP2C9 , Inhibidores Enzimáticos del Citocromo P-450 , Humanos , Concentración 50 Inhibidora , Isoenzimas/antagonistas & inhibidores , Oocitos , Quinolonas/farmacología , Relación Estructura-Actividad , Xenopus laevisRESUMEN
Replacement of the morpholinyl moiety in (S,E)-N-[1-(3-morpholinophenyl)ethyl]-3-phenylacrylamide (1) with heteroaryl groups led to the identification of (S,E)-N-1-[3-(6-fluoropyridin-3-yl)phenyl]ethyl-3-(2-fluorophenyl)acrylamide (5) as a potent KCNQ2 potassium channel opener. Among this series of heteroaryl substituted acrylamides, (S,E)-N-1-[3-(1H-pyrazol-1-yl)phenyl]ethyl-3-(2-fluorophenyl)acrylamide (9) exhibits balanced potency and efficacy. The syntheses and the KCNQ2 opener activity of this series of acrylamides are described.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Canales de Potasio con Entrada de Voltaje/metabolismo , Acrilamidas/síntesis química , Acrilamidas/farmacología , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Canal de Potasio KCNQ2 , Estructura MolecularRESUMEN
A series of Maxi-K openers for the treatment of erectile dysfunction based on the 3-thio-quinolinone core is described. Significant levels of channel opening (up to 550% of control) are seen in transfected oocytes. Functional activity in rabbit corpus cavernosum tissue strips confirms the potential to effect therapy for ED, the effect being maximal for the 3-amino-2-hydroxy thiol side chain.
Asunto(s)
Activación del Canal Iónico , Erección Peniana/efectos de los fármacos , Canales de Potasio Calcio-Activados/efectos de los fármacos , Quinolinas/síntesis química , Sulfuros/síntesis química , Vasodilatadores/síntesis química , Animales , Disfunción Eréctil/tratamiento farmacológico , Humanos , Técnicas In Vitro , Canales de Potasio de Gran Conductancia Activados por el Calcio , Masculino , Relajación Muscular/efectos de los fármacos , Relajación Muscular/fisiología , Músculo Liso Vascular/efectos de los fármacos , Oocitos/efectos de los fármacos , Oocitos/fisiología , Técnicas de Placa-Clamp , Erección Peniana/fisiología , Pene/irrigación sanguínea , Quinolinas/química , Quinolinas/farmacología , Conejos , Relación Estructura-Actividad , Sulfuros/química , Sulfuros/farmacología , Vasodilatadores/química , Vasodilatadores/farmacologíaRESUMEN
Bioisosteric replacement studies led to the identification of N-(1-benzo[1,3]dioxol-5-yl-ethyl)-3-(2-chloro-phenyl)-acrylamide ((S)-3) as a highly potent KCNQ2 opener, and 3-(2,6-difluoro-phenyl)-N-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-acrylamide ((S)-4), and N-[1-(2,3-dihydro-1H-indol-5-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide ((S)-5) as highly efficacious KCNQ2 openers. In contrast, their respective R enantiomers showed significantly less or no appreciable KCNQ2 opener activity even at the highest concentration tested (10 microM). Because of its high potency and moderate efficacy as well as its convenient synthesis, (+/-)-3 was selected as a reference compound for analyzing efficacies of KCNQ openers in electrophysiology studies. Compounds (S)-4 and (S)-5 demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices. The synthesis and the KCNQ2 opener activity of these acrylamides are described.
Asunto(s)
Acrilamidas/química , Benzofuranos/química , Canales de Potasio con Entrada de Voltaje/metabolismo , Acrilamidas/farmacología , Animales , Benzofuranos/farmacología , Línea Celular , Relación Dosis-Respuesta a Droga , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Canal de Potasio KCNQ2 , RatasRESUMEN
A new class of acrylamides was synthesized, and the effects of these analogues on outward potassium current were evaluated by using two electrode voltage clamp recordings from Xenopus laevis oocytes expressing cloned mKCNQ2 channels. SAR studies indicated that the pharmacophore of the acrylamide series includes the (S) absolute configuration at the (1-phenyl)ethyl moiety and the alpha,beta-unsaturated acrylamide functionality with a free NH. This study identified (S)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-acrylamide ((S)-1) and (S)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-ethyl]-3-(4-fluoro-phenyl)-acrylamide ((S)-2) as KCNQ2 openers for further electrophysiological evaluations. These two acrylamides demonstrated significant activity in the cortical spreading depression model of migraine as we reported previously.
Asunto(s)
Acrilamidas/síntesis química , Cinamatos/síntesis química , Morfolinas/síntesis química , Canales de Potasio/efectos de los fármacos , Acrilamidas/química , Acrilamidas/farmacología , Animales , Cinamatos/química , Cinamatos/farmacología , Depresión de Propagación Cortical/efectos de los fármacos , Humanos , Canal de Potasio KCNQ2 , Ratones , Morfolinas/química , Morfolinas/farmacología , Oocitos/efectos de los fármacos , Oocitos/fisiología , Técnicas de Placa-Clamp , Canales de Potasio/fisiología , Canales de Potasio con Entrada de Voltaje , Estereoisomerismo , Relación Estructura-Actividad , Xenopus laevisRESUMEN
(S)-N-[1-(4-Cyclopropylmethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide ((S)-2) was identified as a potent and efficacious KCNQ2 opener. This compound demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices, and the inhibition mediated by (S)-2 was reversed by the KCNQ blocker linopirdine.
Asunto(s)
Acrilamidas/farmacología , Hipocampo/efectos de los fármacos , Neuronas/efectos de los fármacos , Oxazinas/farmacología , Canales de Potasio/efectos de los fármacos , Acrilamidas/síntesis química , Animales , Relación Dosis-Respuesta a Droga , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Canal de Potasio KCNQ2 , Riñón/citología , Riñón/efectos de los fármacos , Riñón/metabolismo , Ratones , Estructura Molecular , Neuronas/metabolismo , Neuronas/patología , Oxazinas/síntesis química , Técnicas de Placa-Clamp , Canales de Potasio/genética , Canales de Potasio/metabolismo , Canales de Potasio con Entrada de Voltaje , Ratas , Relación Estructura-ActividadRESUMEN
Antagonists of serotonin 6 (5-HT6) receptors have been reported to enhance cognition in animal models of learning, although this finding has not been universal. We have assessed the therapeutic potential of the specific 5-HT6 receptor antagonists 4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide (Ro 04-6790) and 5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide (SB-271046) in rodent models of cognitive function. Although mice express the 5-HT6 receptor and the function of this receptor has been investigated in mice, all reports of activity with 5-HT6 receptor antagonists have used rat models. In the present study, receptor binding revealed that the pharmacological properties of the mouse receptor are different from the rat and human receptor: Ro 04-6790 does not bind to the mouse 5-HT6 receptor, so all in vivo testing included in the present report was conducted in rats. We replicated previous reports that 5-HT6 receptor antagonists produce a stretching syndrome previously shown to be mediated through cholinergic mechanisms, but Ro 04-6790 and SB-271046 failed to attenuate scopolamine-induced deficits in a test of contextual fear conditioning. We also failed to replicate the significant effects reported previously in both an autoshaping task and in a version of the Morris water maze. The results of our experiments are not consistent with previous reports that suggested that 5-HT6 antagonists might have therapeutic potential for cognitive disorders.
Asunto(s)
Aprendizaje/efectos de los fármacos , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Sulfonamidas/farmacología , Tiofenos/farmacología , Animales , Sitios de Unión , Humanos , Masticación/efectos de los fármacos , Ratones , Modelos Animales , Pirimidinas/farmacología , Ratas , Ratas Long-Evans , Ratas Sprague-Dawley , Ratas Wistar , Receptores de Serotonina/efectos de los fármacos , Bostezo/efectos de los fármacosRESUMEN
(S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]-3-phenylacrylamide (2) was synthesized as an orally bioavailable KCNQ2 potassium channel opener. In a rat model of migraine, 2 demonstrated significant oral activity in reducing the total number of cortical spreading depressions induced by potassium chloride.
Asunto(s)
Acrilamidas/síntesis química , Corteza Cerebral/efectos de los fármacos , Trastornos Migrañosos/fisiopatología , Morfolinas/síntesis química , Canales de Potasio/efectos de los fármacos , Acrilamidas/química , Acrilamidas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Línea Celular , Corteza Cerebral/fisiopatología , Modelos Animales de Enfermedad , Perros , Humanos , Activación del Canal Iónico , Canal de Potasio KCNQ2 , Trastornos Migrañosos/metabolismo , Morfolinas/química , Morfolinas/farmacología , Oocitos/efectos de los fármacos , Oocitos/fisiología , Técnicas de Placa-Clamp , Canales de Potasio/fisiología , Canales de Potasio con Entrada de Voltaje , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Xenopus laevisRESUMEN
Novel 4-aryl-3-(hydroxyalkyl)quinoline-2-one derivatives were prepared and evaluated as openers of the cloned maxi-K channel hSlo expressed in Xenopus laevis oocytes by utilizing electrophysiological methods. The effect of these maxi-K openers on corporal smooth muscle was studied in vitro using isolated rabbit corpus cavernosum. From this study, a potent maxi-K opener was identified as an effective relaxant of rabbit corporal smooth muscle and shown to be active in an in vivo animal model of male erectile function.
Asunto(s)
Músculo Liso/efectos de los fármacos , Pene/efectos de los fármacos , Canales de Potasio Calcio-Activados/efectos de los fármacos , Quinolonas/síntesis química , Animales , Presión Sanguínea/efectos de los fármacos , Estimulación Eléctrica , Disfunción Eréctil/tratamiento farmacológico , Técnicas In Vitro , Canales de Potasio de Gran Conductancia Activados por el Calcio , Masculino , Relajación Muscular/efectos de los fármacos , Músculo Liso/fisiología , Erección Peniana/efectos de los fármacos , Pene/inervación , Pene/fisiología , Presión , Quinolonas/química , Quinolonas/farmacología , Conejos , Ratas , Ratas Endogámicas F344 , Relación Estructura-ActividadRESUMEN
Electrophysiological evaluation of symmetrical analogues of the known maxi-K opener NS-004 (1) led to the discovery of bisphenols 2a, 3a and 4a as openers of cloned maxi-K channels expressed in oocytes.
Asunto(s)
Fenoles/química , Fenoles/farmacología , Canales de Potasio Calcio-Activados/agonistas , Animales , Bencimidazoles/química , Clorofenoles/química , Relación Dosis-Respuesta a Droga , Electrofisiología , Canales de Potasio de Gran Conductancia Activados por el Calcio , Oocitos/efectos de los fármacos , Oocitos/fisiología , Técnicas de Placa-Clamp , Canales de Potasio Calcio-Activados/efectos de los fármacos , Canales de Potasio Calcio-Activados/fisiología , Xenopus laevisRESUMEN
OBJECTIVE: To investigate the usefulness of a novel retinoic acid receptor (RAR) antagonist (BMS-189453) in animal models of arthritis. METHODS: BMS-189453 was tested in HIG-82 rabbit synovial fibroblasts to determine its ability to repress collagenase (matrix metalloproteinase-1, MMP-1) mRNA expression in vitro. Cells were stimulated with phorbol myristate acetate or interleukin 1 beta and mRNA quantified by slot-blot analysis. In vivo, BMS-189453 was evaluated in 2 animal models of arthritis: collagen induced arthritis (CIA) in mice and streptococcal cell wall induced arthritis (SCWA) in rats. Clinical scores for arthritis were recorded weekly. At the end of each study, limbs were evaluated histologically. In CIA, these results were correlated with mRNA levels for collagenase-3 (MMP-13) and stromelysin-1 (MMP-3) as determined by Northern blot. RESULTS: BMS-189453 reduced MMP-1 expression in HIG-82 synovial fibroblasts in culture. BMS-189453 treatment blocked the clinical progression of arthritis beyond soft tissue inflammation in the CIA model. In the SCWA model, BMS-189453 treatment resulted in significantly reduced swelling with no notable progression to joint distortion/destruction. Histological evaluation of the joints from animals in both models confirmed this result. Analysis of mRNA from the CIA paws showed that BMS-189453 prevented the overexpression of MMP-13 and MMP-3 in arthritic joints. CONCLUSION: Improvement in clinical and histologic variables in 2 separate animal models, along with simultaneous reduction in MMP expression in the affected joint, suggests that RAR antagonists such as BMS-189453 may be useful as agents to treat rheumatoid arthritis and for determining the role of MMP in disease progression. This is the first study to show the clinical potential of RAR antagonists in arthritis.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Retinoides/antagonistas & inhibidores , Retinoides/farmacología , Animales , Artritis Experimental/patología , Carcinógenos/farmacología , Colagenasas/genética , Modelos Animales de Enfermedad , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Técnicas In Vitro , Interleucina-1/farmacología , Metaloproteinasa 1 de la Matriz/genética , Metaloproteinasa 13 de la Matriz , Metaloproteinasa 3 de la Matriz/genética , Ratones , Ratones Endogámicos DBA , Conejos , Ratas , Ratas Endogámicas Lew , Receptores de Ácido Retinoico/antagonistas & inhibidores , Retinoides/química , Membrana Sinovial/citología , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
A series of 4-aryl-3-aminoquinoline-2-one derivatives was synthesized and evaluated as activators of the cloned maxi-K channel mSlo (hSlo) expressed in Xenopus laevis oocytes using electrophysiological methods. A brain penetrable activator of maxi-K channels was identified and shown to be significantly active in the MCAO model of stroke.
Asunto(s)
Fármacos Neuroprotectores/química , Canales de Potasio Calcio-Activados/metabolismo , Quinolonas/química , Animales , Encéfalo/efectos de los fármacos , Células Clonales , Modelos Animales de Enfermedad , Electrofisiología , Canales de Potasio de Gran Conductancia Activados por el Calcio , Masculino , Potenciales de la Membrana , Fármacos Neuroprotectores/sangre , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/farmacología , Oocitos/metabolismo , Técnicas de Placa-Clamp , Canales de Potasio Calcio-Activados/efectos de los fármacos , Quinolonas/sangre , Quinolonas/síntesis química , Quinolonas/farmacología , Ratas , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/tratamiento farmacológico , Relación Estructura-Actividad , Xenopus laevisRESUMEN
A series of diphenyl-substituted heterocycles were synthesized and evaluated by electrophysiological techniques as openers of the cloned mammalian large-conductance, Ca(2+)-activated potassium (maxi-K) channel. The series was designed from deannulation of known benzimidazolone maxi-K opener NS-004 (2) thereby providing an effective template for obtaining structure-activity-related information. The triazolone ring system was the most studied wherein 4,5-diphenyltriazol-3-one 6d (maxi-K = 158%) was identified as the optimal maxi-K channel opener.
Asunto(s)
Canales de Potasio Calcio-Activados/agonistas , Triazoles/síntesis química , Animales , Cristalografía por Rayos X , Técnicas In Vitro , Canales de Potasio de Gran Conductancia Activados por el Calcio , Modelos Moleculares , Conformación Molecular , Oocitos/efectos de los fármacos , Oocitos/fisiología , Técnicas de Placa-Clamp , Canales de Potasio Calcio-Activados/fisiología , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacología , Xenopus laevisRESUMEN
3-Aryl-3-fluorooxindoles can be efficiently synthesized in two steps by the addition of an aryl Grignard to an isatin, followed by treatment with DAST. Oxindole 1 (BMS-204352; MaxiPost) can be isolated using chiral HPLC or prepared by employing chiral resolution. Cloned maxi-K channels are opened by 1, which demonstrates a brain/plasma ratio >9 in rats.
Asunto(s)
Encéfalo/efectos de los fármacos , Compuestos de Diazonio , Indoles/síntesis química , Indoles/farmacología , Oocitos/efectos de los fármacos , Oocitos/fisiología , Canales de Potasio Calcio-Activados/efectos de los fármacos , Animales , Encéfalo/metabolismo , Calcio/metabolismo , Células Cultivadas/efectos de los fármacos , Humanos , Indoles/sangre , Canales de Potasio de Gran Conductancia Activados por el Calcio , Masculino , Microinyecciones , Técnicas de Placa-Clamp , Canales de Potasio Calcio-Activados/genética , Canales de Potasio Calcio-Activados/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , XenopusRESUMEN
A series of 1,3-diaryl 1,2,4-(4H)-triazol-5-ones was prepared and shown by electrophysiological analysis to activate a cloned maxi-K channel mSlo (or hSlo) expressed in Xenopus laevis oocytes. The effects of these structurally novel maxi-K channel openers on bladder contractile function were studied in vitro using isolated rat bladder strips pre-contracted with carbachol. Several 1,3-diaryl 1,2,4-(4H)-triazol-5-one derivatives were found to be potent smooth muscle relaxants but this activity did not completely correlate with maxi-K channel opening.