RESUMO
Screening of 100 acylsulfonamides from the Bristol-Myers Squibb compound collection identified the C3-cyclohexyl indole 6 as a potent Nav1.7 inhibitor. Replacement of the C2 furanyl ring of 6 with a heteroaryl moiety or truncation of this group led to the identification of 4 analogs with hNav1.7 IC50 values under 50â¯nM. Fluorine substitution of the truncated compound 12 led to 34 with improved potency and isoform selectivity. The inverted indole 36 also maintained good activity. Both 34 and 36 exhibited favorable CYP inhibition profiles, good membrane permeability and a low efflux ratio and, therefore, represent new leads in the search for potent and selective Nav1.7 inhibitors to treat pain.
Assuntos
Descoberta de Drogas , Indóis/química , Canal de Sódio Disparado por Voltagem NAV1.7/efeitos dos fármacos , Sulfonamidas/farmacologia , Humanos , Concentração Inibidora 50 , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Replacement of the piperidine ring in the lead benzenesulfonamide Nav1.7 inhibitor 1 with a weakly basic morpholine core resulted in a significant reduction in Nav1.7 inhibitory activity, but the activity was restored by shortening the linkage from methyleneoxy to oxygen. These efforts led to a series of morpholine-based aryl sulfonamides as isoform-selective Nav1.7 inhibitors. This report describes the synthesis and SAR of these analogs.
Assuntos
Morfolinas/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Sulfonamidas/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Morfolinas/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/químicaRESUMO
The NaV1.7 voltage-gated sodium channel is implicated in human pain perception by genetics. Rare gain of function mutations in NaV1.7 lead to spontaneous pain in humans whereas loss of function mutations results in congenital insensitivity to pain. Hence, agents that specifically modulate the function of NaV1.7 have the potential to yield novel therapeutics to treat pain. The complexity of the channel and the challenges to generate recombinant cell lines with high NaV1.7 expression have led to a surrogate target strategy approach employing chimeras with the bacterial channel NaVAb. In this report we describe the design, synthesis, purification, and characterization of a chimera containing part of the voltage sensor domain 2 (VSD2) of NaV1.7. Importantly, this chimera, DII S1-S4, forms functional sodium channels and is potently inhibited by the NaV1.7 VSD2 targeted peptide toxin ProTx-II. Further, we show by [125I]ProTx-II binding and surface plasmon resonance that the purified DII S1-S4 protein retains high affinity ProTx-II binding in detergent. We employed the purified DII S1-S4 protein to create a scintillation proximity assay suitable for high-throughput screening. The creation of a NaV1.7-NaVAb chimera with the VSD2 toxin binding site provides an important tool for the identification of novel NaV1.7 inhibitors and for structural studies to understand the toxin-channel interaction.
Assuntos
Proteínas de Bactérias/química , Canal de Sódio Disparado por Voltagem NAV1.7/fisiologia , Proteínas Recombinantes de Fusão/química , Venenos de Aranha/metabolismo , Canais de Sódio Disparados por Voltagem/química , Proteínas de Bactérias/fisiologia , Sítios de Ligação , Células HEK293 , Humanos , Ressonância de Plasmônio de Superfície , Canais de Sódio Disparados por Voltagem/fisiologiaRESUMO
A series of substituted pyridines, ether linked to a phenylpiperidine core were optimized for dual NK(1)/SERT affinity. Optimization based on NK(1)/SERT binding affinities, and minimization of off-target ion channel activity lead to the discovery of compound 44. In vivo evaluation of 44 in the gerbil forced swim test (a depression model), and ex-vivo NK(1)/SERT receptor occupancy data support the potential of a dual acting compound for the treatment of depression.
Assuntos
Depressão/tratamento farmacológico , Desenho de Fármacos , Antagonistas dos Receptores de Neurocinina-1 , Piridinas/síntese química , Antagonistas da Serotonina , Animais , Modelos Animais de Doenças , Gerbillinae , Concentração Inibidora 50 , Estrutura Molecular , Piridinas/química , Piridinas/uso terapêutico , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Antagonistas da Serotonina/uso terapêuticoRESUMO
3-Aryl-indole and 3-aryl-indazole derivatives were identified as potent and selective Nav1.7 inhibitors. Compound 29 was shown to be efficacious in the mouse formalin assay and also reduced complete Freund's adjuvant (CFA)-induced thermal hyperalgesia and chronic constriction injury (CCI) induced cold allodynia and models of inflammatory and neuropathic pain, respectively, following intraperitoneal (IP) doses of 30 mg/kg. The observed efficacy could be correlated with the mouse dorsal root ganglion exposure and NaV1.7 potency associated with 29.
Assuntos
Indazóis/química , Indóis/química , Canal de Sódio Disparado por Voltagem NAV1.7/química , Neuralgia/tratamento farmacológico , Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Meia-Vida , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/patologia , Masculino , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Neuralgia/patologia , Técnicas de Patch-Clamp , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/metabolismoRESUMO
BACKGROUND: A significant proportion of patients suffering from major depression fail to remit following treatment and develop treatment-resistant depression. Developing novel treatments requires animal models with good predictive validity. MRL/lpr mice, an established model of systemic lupus erythematosus, show depression-like behavior. AIMS: We evaluated responses to classical antidepressants, and associated immunological and biochemical changes in MRL/lpr mice. METHODS AND RESULTS: MRL/lpr mice showed increased immobility in the forced swim test, decreased wheel running and sucrose preference when compared with the controls, MRL/MpJ mice. In MRL/lpr mice, acute fluoxetine (30âmg/kg, intraperitoneally (i.p.)), imipramine (10âmg/kg, i.p.) or duloxetine (10âmg/kg, i.p.) did not decrease the immobility time in the Forced Swim Test. Interestingly, acute administration of combinations of olanzapine (0.03âmg/kg, subcutaneously)+fluoxetine (30âmg/kg, i.p.) or bupropion (10âmg/kg, i.p.)+fluoxetine (30âmg/kg, i.p.) retained efficacy. A single dose of ketamine but not three weeks of imipramine (10âmg/kg, i.p.) or escitalopram (5âmg/kg, i.p.) treatment in MRL/lpr mice restored sucrose preference. Further, we evaluated inflammatory, immune-mediated and neuronal mechanisms. In MRL/lpr mice, there was an increase in autoantibodies' titers, [3H]PK11195 binding and immune complex deposition. There was a significant infiltration of the brain by macrophages, neutrophils and T-lymphocytes. p11 mRNA expression was decreased in the prefrontal cortex. Further, there was an increase in the 5-HT2aR expression, plasma corticosterone and indoleamine 2,3-dioxygenase activity. CONCLUSION: In summary, the MRL/lpr mice could be a useful model for Treatment Resistant Depression associated with immune dysfunction with potential to expedite antidepressant drug discovery.
Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Modelos Animais de Doenças , Ketamina/uso terapêutico , Lúpus Eritematoso Sistêmico/complicações , Animais , Corticosterona/sangue , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos MRL lpr , Receptor 5-HT2A de Serotonina/análiseRESUMO
Two high-affinity, G protein-coupled melatonin receptor subtypes have been identified in mammals. Targeted disruption of the Mel(1a) melatonin receptor prevents some, but not all, responses to the hormone, suggesting functional redundancy among receptor subtypes (Liu et al., Neuron 19:91-102, 1997). In the present work, the mouse Mel(1b) melatonin receptor cDNA was isolated and characterized, and the gene has been disrupted. The cDNA encodes a receptor with high affinity for melatonin and a pharmacological profile consistent with its assignment as encoding a melatonin receptor. Mice with targeted disruption of the Mel(1b) receptor have no obvious circadian phenotype. Melatonin suppressed multiunit electrical activity in the suprachiasmatic nucleus (SCN) in Mel(1b) receptor-deficient mice as effectively as in wild-type controls. The neuropeptide, pituitary adenylyl cyclase activating peptide, increases the level of phosphorylated cyclic AMP response element binding protein (CREB) in SCN slices, and melatonin reduces this effect. The Mel(1a) receptor subtype mediates this inhibitory response at moderate ligand concentrations (1 nM). A residual response apparent in Mel(1a) receptor-deficient C3H mice at higher melatonin concentrations (100 nM) is absent in Mel(1a)-Mel(1b) double-mutant mice, indicating that the Mel(1b) receptor mediates this effect of melatonin. These data indicate that there is a limited functional redundancy between the receptor subtypes in the SCN. Mice with targeted disruption of melatonin receptor subtypes will allow molecular dissection of other melatonin receptor-mediated responses.
Assuntos
Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética , Receptores Citoplasmáticos e Nucleares/deficiência , Receptores Citoplasmáticos e Nucleares/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , DNA Complementar/genética , DNA Complementar/isolamento & purificação , Marcação de Genes , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Fenótipo , Fosforilação , Receptores de Melatonina , Homologia de Sequência de Aminoácidos , Núcleo Supraquiasmático/efeitos dos fármacos , Núcleo Supraquiasmático/metabolismoRESUMO
Approximately 30-60% of patients treated with existing antidepressants fail to achieve remission of depressive symptoms leading to Treatment Resistant Depression (TRD). There is an urgent need to develop novel medications, which is highly limited by the non-availability of relevant animal models with good predictive validity. ACTH administration has been shown to result in the resistance to acute and chronic effects of imipramine. However, the pharmacology of the model and the mechanisms contributing to the resistance are not completely understood. Furthermore, it is not known whether the ACTH administered animals show signs of depression-like behavior. Accordingly, we characterized the behavioral profile and sensitivity to antidepressants in BALB/c mice treated with ACTH and to evaluate some of the mechanisms responsible for the behavioral effects. Daily treatment with ACTH for 14, 21 or 28days failed to produce a depression-like phenotype in the sucrose preference test, voluntary wheel running or FST. In contrast, the acute antidepressant response in the FST was no longer observed in ACTH mice treated with fluoxetine, imipramine, duloxetine or bupropion. Interestingly, the combination of fluoxetine and a low dose of olanzapine, or the combination of fluoxetine and bupropion was efficacious in ACTH treated mice. Further, the sensitivity to a GluN2B receptor antagonist, radiprodil was retained in the ACTH model. To understand the mechanism responsible for the diminished response in these mice, we evaluated p11 (S100A10) mRNA expression and 5-HT2A protein expression. p11 expression was decreased and 5-HT2A protein content increased in ACTH treated mice. In summary, this model may have utility for the identification of novel treatments for TRD.
Assuntos
Hormônio Adrenocorticotrópico/administração & dosagem , Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Modelos Animais de Doenças , Atividade Motora/efeitos dos fármacos , Hormônio Adrenocorticotrópico/toxicidade , Animais , Anexina A2/biossíntese , Antidepressivos/farmacologia , Transtorno Depressivo Resistente a Tratamento/induzido quimicamente , Transtorno Depressivo Resistente a Tratamento/metabolismo , Relação Dose-Resposta a Droga , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Atividade Motora/fisiologia , Receptor 5-HT2A de Serotonina/biossíntese , Proteínas S100/biossínteseRESUMO
The alpha7 (α7) nicotinic acetylcholine receptor is a therapeutic target for cognitive disorders. Here we describe 3-(3,4-difluorophenyl)-N-(1-(6-(4-(pyridin-2-yl)piperazin-1-yl)pyrazin-2-yl)ethyl)propanamide (B-973), a novel piperazine-containing molecule that acts as a positive allosteric modulator of the α7 receptor. We characterize the action of B-973 on the α7 receptor using electrophysiology and radioligand binding. At 0.1mM acetylcholine, 1µM B-973 potentiated peak acetylcholine-induced currents 6-fold relative to maximal acetylcholine (3mM) and slowed channel desensitization, resulting in a 6900-fold increase in charge transfer. The EC50 of B-973 was approximately 0.3µM at acetylcholine concentrations ranging from 0.03 to 3mM. At a concentration of 1µM, B-973 shifted the acetylcholine EC50 of peak currents from 0.30mM in control to 0.007mM. B-973 slowed channel deactivation upon acetylcholine removal (τ=50s) and increased the affinity of the α7 agonist [3H]A-585539. In the absence of exogenously added acetylcholine, application of B-973 at concentrations >1µM induced large methyllycaconitine-sensitive currents, suggesting B-973 can function as an Ago-PAM at high concentrations. B-973 will be a useful probe for investigating the biological consequences of increasing α7 receptor activity through allosteric modulation.
Assuntos
Fenilpropionatos/farmacologia , Piperazinas/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Acetilcolina/farmacologia , Regulação Alostérica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Descoberta de Drogas , Células HEK293 , Humanos , CinéticaRESUMO
By taking advantage of certain features in piperidine 4, we developed a novel series of cyclohexylamine- and piperidine-based benzenesulfonamides as potent and selective Nav1.7 inhibitors. However, compound 24, one of the early analogs, failed to reduce phase 2 flinching in the mouse formalin test even at a dose of 100 mpk PO due to insufficient dorsal root ganglion (DRG) exposure attributed to poor membrane permeability. Two analogs with improved membrane permeability showed much increased DRG concentrations at doses of 30 mpk PO, but, confoundingly, only one of these was effective in the formalin test. More data are needed to understand the disconnect between efficacy and exposure relationships.
Assuntos
Analgésicos/química , Analgésicos/uso terapêutico , Dor/tratamento farmacológico , Sulfonamidas/química , Sulfonamidas/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Descoberta de Drogas , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Dor/metabolismo , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , BenzenossulfonamidasRESUMO
The α7 nicotinic acetylcholine receptor is thought to play an important role in human cognition. Here we describe the in vivo effects of BMS-902483, a selective potent α7 nicotinic acetylcholine receptor partial agonist, in relationship to α7 nicotinic acetylcholine receptor occupancy. BMS-902483 has low nanomolar affinity for rat and human α7 nicotinic acetylcholine receptors and elicits currents in cells expressing human or rat α7 nicotinic acetylcholine receptors that are about 60% of the maximal acetylcholine response. BMS-902483 improved 24h novel object recognition memory in mice with a minimal effective dose (MED) of 0.1mg/kg and reversed MK-801-induced deficits in a rat attentional set-shifting model of executive function with an MED of 3mg/kg. Enhancement of novel object recognition was blocked by the silent α7 nicotinic acetylcholine receptor agonist, NS6740, demonstrating that activity of BMS-902483 was mediated by α7 nicotinic acetylcholine receptors. BMS-902483 also reversed ketamine-induced deficits in auditory gating in rats, and enhanced ex vivo hippocampal long-term potentiation examined 24h after dosing in mice. Results from an ex vivo brain homogenate binding assay showed that α7 receptor occupancy ranged from 64% (novel object recognition) to ~90% (set shift and gating) at the MED for behavioral and sensory processing effects of BMS-902483.
Assuntos
Cognição/efeitos dos fármacos , Agonismo Parcial de Drogas , Agonistas Nicotínicos/farmacologia , Quinuclidinas/farmacologia , Filtro Sensorial/efeitos dos fármacos , Compostos de Espiro/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Animais , Atenção/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos , RatosRESUMO
Combination studies of neurokinin 1 (NK1) receptor antagonists and serotonin-selective reuptake inhibitors (SSRIs) have shown promise in preclinical models of depression. Such a combination may offer important advantages over the current standard of care. Herein we describe the discovery and optimization of an indazole-based chemotype to provide a series of potent dual NK1 receptor antagonists/serotonin transporter (SERT) inhibitors to overcome issues of ion channel blockade. This effort culminated in the identification of compound 9, an analogue that demonstrated favorable oral bioavailability, excellent brain uptake, and robust in vivo efficacy in a validated depression model. Over the course of this work, a novel heterocycle-directed asymmetric hydrogenation was developed to facilitate installation of the key stereogenic center.
Assuntos
Antidepressivos/farmacologia , Indazóis/farmacologia , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Administração Oral , Animais , Antidepressivos/síntese química , Antidepressivos/química , Antidepressivos/toxicidade , Transtorno Depressivo/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Gerbillinae , Humanos , Indazóis/síntese química , Indazóis/química , Indazóis/toxicidade , Camundongos , Estrutura Molecular , Antagonistas dos Receptores de Neurocinina-1/síntese química , Antagonistas dos Receptores de Neurocinina-1/química , Antagonistas dos Receptores de Neurocinina-1/toxicidade , Ratos , Receptores da Neurocinina-1/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/toxicidade , Relação Estrutura-Atividade , Regulador Transcricional ERG/metabolismoRESUMO
The known interactions between the serotonergic and neurokinin systems suggest that serotonin reuptake inhibitor (SSRIs) efficacy may be improved by neurokinin-1 receptor (NK1R) antagonism. In the current studies combination of a subeffective dose of an SSRI (0.3 mg/kg fluoxetine or 0.03 mg/kg citalopram) with a subeffective dose of an NK1R antagonist (0.3 mg/kg aprepitant or 1 mg/kg CP-122,721) produced efficacy in the gerbil forced swim test (FST). Serotonin transporter (SERT) occupancy produced by 1 mg/kg fluoxetine (lowest efficacious dose) was 52 ± 5% and was reduced to 29 ± 4% at 0.3 mg/kg, a dose that was efficacious in combination with 0.3 mg/kg aprepitant or 1 mg/kg CP-122,721; the corresponding NK1R occupancies were 79 ± 4% and 61 ± 4% for aprepitant and CP-122,721, respectively. For citalopram, SERT occupancy at the lowest efficacious dose (0.1 mg/kg) was 50 ± 4% and was reduced to 20 ± 5% at 0.03 mg/kg, a dose that was efficacious when combined with aprepitant (0.3 mg/kg). Aprepitant (10 mg/kg) augmented the serotonin elevation produced by fluoxetine (1 or 10 mg/kg) in the gerbil prefrontal cortex; i.e. NK1R antagonism can modulate serotonin responses. A novel orally-available dual-acting NK1R antagonist/SERT inhibitor BMS-795176 is described; gerbil Ki = 1.4 and 1 nM at NK1R and SERT, respectively. BMS-795176 was efficacious in the gerbil FST; efficacy was observed with 35 ± 3% SERT occupancy and 73 ± 3% NK1R occupancy. The interaction between NK1R antagonism and SERT inhibition to lower the SERT occupancy required for antidepressant-like efficacy suggests that BMS-795176 has the potential to improve efficacy with a reduction in SSRI-associated side effects.
Assuntos
Citalopram/farmacologia , Fluoxetina/farmacologia , Morfolinas/farmacologia , Piperidinas/farmacologia , Receptores da Neurocinina-1/metabolismo , Animais , Antidepressivos/farmacologia , Aprepitanto , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Gerbillinae , Células HEK293 , Humanos , Resposta de Imobilidade Tônica/efeitos dos fármacos , Masculino , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ensaio Radioligante , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
The effect of gamma-aminobutyric acid (GABA) on neuronal firing rate in rat suprachiasmatic nucleus (SCN) slices was examined using continuous recording methods. GABA inhibited neuronal discharge during both the subjective day and the subjective night in a concentration-dependent manner characterized by two apparent affinity states. The GABAA receptor agonist muscimol caused potent inhibition regardless of circadian time; repeated applications of the agonist did not reverse the direction of effect. The GABAA receptor antagonists bicuculline and picrotoxin increased excitability when applied during either subjective day or subjective night. A significant increase in GABAA receptor- mediated inhibition, as well as endogenous GABAergic tone, was observed on the second day after slice preparation. The GABAB receptor agonist baclofen inhibited cell firing during subjective day and night, but the GABAB antagonist phaclofen had no significant effect. These data provide additional strong support for a predominantly inhibitory role of GABA in the rat SCN, regardless of the time of application in relation to the circadian rhythm, and demonstrate an important level of plasticity of this system in vitro.
Assuntos
Potenciais de Ação/fisiologia , Ritmo Circadiano/fisiologia , Inibição Neural/fisiologia , Receptores de GABA/fisiologia , Núcleo Supraquiasmático/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Ritmo Circadiano/efeitos dos fármacos , Relação Dose-Resposta a Droga , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Técnicas In Vitro , Masculino , Inibição Neural/efeitos dos fármacos , Ratos , Ratos Long-Evans , Núcleo Supraquiasmático/efeitos dos fármacosRESUMO
(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.
Assuntos
Acrilamidas/farmacologia , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Oxazinas/farmacologia , Canais de Potássio/efeitos dos fármacos , Acrilamidas/síntese química , Animais , Relação Dose-Resposta a Droga , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Canal de Potássio KCNQ2 , Rim/citologia , Rim/efeitos dos fármacos , Rim/metabolismo , Camundongos , Estrutura Molecular , Neurônios/metabolismo , Neurônios/patologia , Oxazinas/síntese química , Técnicas de Patch-Clamp , Canais de Potássio/genética , Canais de Potássio/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Ratos , Relação Estrutura-AtividadeRESUMO
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.