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1.
J Med Chem ; 64(4): 1873-1888, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33588527

RESUMO

Accumulation of amyloid ß peptides (Aß) is thought to be one of the causal factors of Alzheimer's disease (AD). The aspartyl protease ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting protease for Aß production, and therefore, BACE1 inhibition is a promising therapeutic approach for the treatment of AD. Starting with a dihydro-1,3-thiazine-based lead, Compound J, we discovered atabecestat 1 (JNJ-54861911) as a centrally efficacious BACE1 inhibitor that was advanced into the EARLY Phase 2b/3 clinical trial for the treatment of preclinical AD patients. Compound 1 demonstrated robust and dose-dependent Aß reduction and showed sufficient safety margins in preclinical models. The potential of reactive metabolite formation was evaluated in a covalent binding study to assess its irreversible binding to human hepatocytes. Unfortunately, the EARLY trial was discontinued due to significant elevation of liver enzymes, and subsequent analysis of the clinical outcomes showed dose-related cognitive worsening.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores de Proteases/uso terapêutico , Piridinas/uso terapêutico , Tiazinas/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Animais , Cães , Canal de Potássio ERG1/antagonistas & inibidores , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Masculino , Camundongos , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Ratos Sprague-Dawley , Tiazinas/síntese química , Tiazinas/farmacocinética
2.
ChemMedChem ; 14(22): 1894-1910, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31657130

RESUMO

The ß-site amyloid precursor protein cleaving enzyme 1 (BACE1, also known as ß-secretase) is a promising target for the treatment of Alzheimer's disease. A pKa lowering approach over the initial leads was adopted to mitigate hERG inhibition and P-gp efflux, leading to the design of 6-CF3 dihydrothiazine 8 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide). Optimization of 8 led to the discovery of 15 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)pyrazine-2-carboxamide) with an excellent balance of potency, hERG inhibition, P-gp efflux, and metabolic stability. Oral administration of 8 elicited robust Aß reduction in dog even at 0.16 mg/kg. Reflecting the reduced hERG inhibitory activity, no QTc prolongation was observed at high doses. The potential for reactive metabolite formation of 15 was realized in a nucleophile trapping assay using [14 C]-KCN in human liver microsomes. Utilizing covalent binding (CVB) in human hepatocytes and the maximum projected human dosage, the daily CVB burden of 15 was calculated to be at an acceptable value of below 1 mg/day. However, hepatotoxicity was observed when 15 was subjected to a two-week tolerance study in dog, which prevented further evaluation of this compound.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Oxazinas/farmacologia , Tiazinas/farmacologia , Secretases da Proteína Precursora do Amiloide/deficiência , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/deficiência , Ácido Aspártico Endopeptidases/metabolismo , Cães , Relação Dose-Resposta a Droga , Desenho de Fármacos , Hepatócitos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Knockout , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Oxazinas/química , Ratos , Relação Estrutura-Atividade , Tiazinas/administração & dosagem , Tiazinas/química
3.
J Med Chem ; 62(20): 9331-9337, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31549838

RESUMO

Genetic evidence points to deposition of amyloid-ß (Aß) as a causal factor for Alzheimer's disease. Aß generation is initiated when ß-secretase (BACE1) cleaves the amyloid precursor protein. Starting with an oxazine lead 1, we describe the discovery of a thiazine-based BACE1 inhibitor 5 with robust Aß reduction in vivo at low concentrations, leading to a low projected human dose of 14 mg/day where 5 achieved sustained Aß reduction of 80% at trough level.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores de Proteases/química , Tiazinas/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Citocromo P-450 CYP2C9/química , Citocromo P-450 CYP2C9/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Meia-Vida , Haplorrinos , Coração/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Ratos , Ratos Sprague-Dawley , Tiazinas/metabolismo , Tiazinas/farmacologia
4.
PLoS One ; 14(8): e0221205, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31430310

RESUMO

Methamphetamine (METH), a commonly abused drug, elevates extracellular dopamine (DA) levels by inducing DA efflux through the DA transporter (DAT). Emerging evidence in rodent models suggests that locomotor responses to a novel inescapable open field may predict behavioral responses to abused drugs; METH produces more potent stimulant effects in high responders to novelty than in low responders. We herein found that mice deficient in protein tyrosine phosphatase receptor type Z (Ptprz-KO) exhibited an enhanced behavioral response to novelty; however, METH-induced hyperlocomotion was significantly lower in Ptprz-KO than in wild-type mice when METH was administered at a non-toxic dose of 1 mg per kg body weight (bdw). Single-cell RT-PCR revealed that the majority of midbrain DA neurons expressed PTPRZ. No histological alterations were observed in the mesolimbic or nigrostriatal dopaminergic pathways in Ptprz-KO brains; however, a significant decrease was noted in brain DA turnover, suggesting functional alterations. In vivo microdialysis experiments revealed that METH-evoked DA release in the nucleus accumbens was significantly lower in Ptprz-KO mice than in wild-type mice. Consistent with this result, Ptprz-KO mice showed significantly fewer cell surface DAT as well as weaker DA uptake activity in striatal synaptosomes prepared 1 hr after the administration of METH than wild-type mice, while no significant differences were observed in the two groups treated with saline. These results indicate that the high response phenotype of Ptprz-KO mice to novelty may not be simply attributed to hyper-dopaminergic activity, and that deficits in PTPRZ reduce the effects of METH by reducing DAT activity.


Assuntos
Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Comportamento Exploratório , Metanfetamina/farmacologia , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/genética , Animais , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/genética , Masculino , Camundongos , Camundongos Knockout , Modelos Animais , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/metabolismo
5.
Brain Res ; 1715: 35-40, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30898673

RESUMO

The mechanisms underlying central post-stroke pain are not well understood and there is no satisfactory treatment. Here, in a rat model of stroke, we measured nociceptive threshold using current stimulation of primary afferent neurons in both hind paws. Male Wistar rats underwent middle cerebral artery occlusion (MCAO) for 50 min. Nociceptive thresholds for Aß, Aδ and C fiber stimulation (at 2000, 250, and 5 Hz, respectively, using a Neurometer), and neurological deficits, were measured for 23 days after MCAO. Sensory thresholds in both hind paws were significantly lower in MCAO model rats than in control rats for 23 days after MCAO, with the greatest difference seen in Aδ fibers and the smallest in C fibers. Brain infarct area was measured histologically, and the correlation between neurological deficit and infarct size was examined. Neurological deficits were worse in animals with larger infarcts. Furthermore, correlations were observed between infarct size, neurological deficit, and sensory threshold of Aδ fibers 1 day after MCAO. These findings indicate that rats develop hyperalgesia after MCAO and that sensory abnormalities in Aδ fibers after cerebral ischemia may play an important role in post-stroke pain.


Assuntos
Hiperalgesia/fisiopatologia , Neurônios Aferentes/fisiologia , Dor Nociceptiva/fisiopatologia , Animais , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Ataque Isquêmico Transitório/patologia , Masculino , Nociceptores/fisiologia , Dor/fisiopatologia , Ratos , Ratos Wistar , Acidente Vascular Cerebral/fisiopatologia
6.
Eur J Pharmacol ; 833: 263-274, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-29886243

RESUMO

Microglia exhibit various activation phenotypes in the spinal cord after peripheral nerve injury, and promote neuropathic pain. Ibudilast is a phosphodiesterase inhibitor with anti-inflammatory activity, but its effect on activated microglia in chronic neuropathic pain is poorly understood. We investigated whether ibudilast was effective on established allodynia associated with activated microglial phenotypes in two rat models of peripheral and central neuropathic pain. A single intrathecal injection of ibudilast (25 µg) inhibited established allodynia on days 7-21 after sciatic nerve injury in rats. Repeated injections of ibudilast (25 µg/day) reduced the numbers of phosphorylated p38-positive cells without changing hypertrophic microglia, whereas minocycline (100 µg/day) decreased the numbers of hypertrophic microglia associated with phosphorylated p38 levels in the spinal cord. Gene analysis revealed that minocycline, but not ibudilast, increased the expression of anti-inflammatory cytokine genes Il10 and Tgfß1 in the spinal cord. Propentofylline (100 µg/day) was less effective on microglial phenotypes and established allodynia. Ibudilast inhibited persistent allodynia after the recovery of motor deficits in experimental autoimmune encephalomyelitis rats. Therefore, ibudilast might be effective for chronic neuropathic pain after peripheral and central nerve damage. Ibudilast mediated these effects on activated microglia using a different mechanism compared with minocycline and propentofylline.


Assuntos
Hiperalgesia/tratamento farmacológico , Microglia/efeitos dos fármacos , Neuralgia/tratamento farmacológico , Inibidores de Fosfodiesterase/farmacologia , Piridinas/farmacologia , Animais , Encefalomielite Autoimune Experimental/complicações , Encefalomielite Autoimune Experimental/etiologia , Feminino , Humanos , Hiperalgesia/etiologia , Injeções Espinhais , Masculino , Minociclina/farmacologia , Neuralgia/etiologia , Fármacos Neuroprotetores/farmacologia , Medição da Dor , Traumatismos dos Nervos Periféricos/complicações , Traumatismos dos Nervos Periféricos/etiologia , Inibidores de Fosfodiesterase/uso terapêutico , Fosforilação , Piridinas/uso terapêutico , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Nervo Isquiático/lesões , Medula Espinal/citologia , Xantinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
J Med Chem ; 61(12): 5122-5137, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29733614

RESUMO

Accumulation of Aß peptides is a hallmark of Alzheimer's disease (AD) and is considered a causal factor in the pathogenesis of AD. ß-Secretase (BACE1) is a key enzyme responsible for producing Aß peptides, and thus agents that inhibit BACE1 should be beneficial for disease-modifying treatment of AD. Here we describe the discovery and optimization of novel oxazine-based BACE1 inhibitors by lowering amidine basicity with the incorporation of a double bond to improve brain penetration. Starting from a 1,3-dihydrooxazine lead 6 identified by a hit-to-lead SAR following HTS, we adopted a p Ka lowering strategy to reduce the P-gp efflux and the high hERG potential leading to the discovery of 15 that produced significant Aß reduction with long duration in pharmacodynamic models and exhibited wide safety margins in cardiovascular safety models. This compound improved the brain-to-plasma ratio relative to 6 by reducing P-gp recognition, which was demonstrated by a P-gp knockout mouse model.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Oxazinas/química , Fragmentos de Peptídeos/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Secretases da Proteína Precursora do Amiloide/química , Animais , Ácido Aspártico Endopeptidases/química , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cristalografia por Raios X , Cães , Desenho de Fármacos , Canal de Potássio ERG1/metabolismo , Cobaias , Humanos , Células Madin Darby de Rim Canino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxazinas/farmacologia , Inibidores de Proteases/farmacocinética , Relação Estrutura-Atividade
8.
J Med Chem ; 61(13): 5525-5546, 2018 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-29775538

RESUMO

ß-Secretase (BACE1) has an essential role in the production of amyloid ß peptides that accumulate in patients with Alzheimer's disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying approach for the treatment of AD. Our hit-to-lead efforts led to a cellular potent 1,3-dihydro-oxazine 6, which however inhibited hERG and showed high P-gp efflux. The close analogue of 5-fluoro-oxazine 8 reduced P-gp efflux; further introduction of electron withdrawing groups at the 6-position improved potency and also mitigated P-gp efflux and hERG inhibition. Changing to a pyrazine followed by optimization of substituents on both the oxazine and the pyrazine culminated in 24 with robust Aß reduction in vivo at low doses as well as reduced CYP2D6 inhibition. On the basis of the X-ray analysis and the QM calculation of given dihydro-oxazines, we reasoned that the substituents at the 6-position as well as the 5-fluorine on the oxazine would stabilize a bioactive conformation to increase potency.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Oxazinas/química , Oxazinas/farmacologia , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Humanos , Simulação de Acoplamento Molecular , Oxazinas/metabolismo , Oxazinas/farmacocinética , Conformação Proteica , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Distribuição Tecidual
9.
Pain ; 159(5): 939-947, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29438227

RESUMO

Transient receptor potential vanilloid 4 (TRPV4) receptor modulates pain, and this has been noted in several animal models. However, the involvement of TRPV4 in osteoarthritic (OA) pain remains poorly understood. This study assessed the functional changes in TRPV4 and the expression of its endogenous ligand 5,6-epoxyeicosatrienoic acid (5,6-EET) in a rat monoiodoacetate (MIA)-induced OA pain model (MIA rats). Monoiodoacetate-treated rats showed reduced grip strength as compared to sham-treated rats, and this loss in function could be recovered by the intraarticular administration of a TRPV4 antagonist (HC067047 or GSK2193874). By contrast, the intraarticular administration of the TRPV4 agonist, GSK1016790A, increased the pain-related behaviors in MIA rats but not in sham rats. TRPV4 expression was not increased in knee joints of MIA rats; however, the levels of phosphorylated TRPV4 at Ser824 were increased in dorsal root ganglion neurons. In addition, 5,6-EET was increased in lavage fluids from the knee joints of MIA rats and in meniscectomy-induced OA pain model rats. 5,6-EET and its metabolite were also detected in synovial fluids from patients with OA. In conclusion, TRPV4 was sensitized in the knee joints of MIA rats through phosphorylation in dorsal root ganglion neurons, along with an increase in the levels of its endogenous ligand 5,6-EET. The analgesic effects of the TRPV4 antagonist in the OA pain model rats suggest that TRPV4 may be a potent target for OA pain relief.


Assuntos
Artrite Experimental/metabolismo , Osteoartrite/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Artrite Experimental/induzido quimicamente , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Força da Mão , Ácido Iodoacético , Leucina/análogos & derivados , Leucina/farmacologia , Masculino , Morfolinas/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Osteoartrite/induzido quimicamente , Dor , Medição da Dor , Fosforilação , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores
10.
Cell Rep ; 21(1): 259-273, 2017 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-28978478

RESUMO

γ-secretase inhibitors (GSI) are drugs developed to decrease amyloid-ß peptide (Aß) production by inhibiting intramembranous cleavage of ß-amyloid protein precursor (ßAPP). However, a large phase 3 trial of semagacestat, a potential non-transition state analog (non-TSA) GSI, in patients with Alzheimer's disease (AD) was terminated due to unexpected aggravation of cognitive deficits and side effects. Here, we show that some semagacestat effects are clearly different from a phenotype caused by a loss of function of presenilins, core proteins in the γ-secretase complex. Semagacestat increases intracellular byproduct peptides, produced along with Aß through serial γ-cleavage of ßAPP, as well as intracellular long Aß species, in cell-based and in vivo studies of AD model mice. Other potential non-TSA GSIs, but not L685,458, a TSA GSI, have similar effects. Furthermore, semagacestat inhibits release of de novo intramembranous γ-byproducts to the soluble space. Thus, semagacestat is a pseudo-GSI, and therefore, the semagacestat clinical trial did not truly test the Aß hypothesis.


Assuntos
Alanina/análogos & derivados , Secretases da Proteína Precursora do Amiloide/genética , Azepinas/farmacologia , Inibidores Enzimáticos/farmacologia , Neurônios/efeitos dos fármacos , Alanina/farmacologia , Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Carbamatos/farmacologia , Diferenciação Celular , Ensaios Clínicos como Assunto , Dipeptídeos/farmacologia , Modelos Animais de Doenças , Esquema de Medicação , Regulação da Expressão Gênica , Células HEK293 , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/enzimologia , Camundongos , Neurônios/enzimologia , Neurônios/patologia
11.
Bioorg Med Chem ; 25(7): 2177-2190, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28284871

RESUMO

A novel series of (6-aminopyridin-3-yl)(4-(pyridin-2-yl)piperazin-1-yl) methanone derivatives were identified as selective transient receptor potential vanilloid 4 (TRPV4) channel antagonist and showed analgesic effect in Freund's Complete Adjuvant (FCA) induced mechanical hyperalgesia model in guinea pig and rat. Modification of right part based on the compound 16d which was disclosed in our previous communication led to the identification of compound 26i as a flagship compound. In this paper, we described the details about design, synthesis and structure-activity relationship (SAR) analysis at right and left part of these derivatives (Fig. 1).


Assuntos
Analgésicos/farmacologia , Compostos Azabicíclicos/farmacologia , Manejo da Dor/métodos , Canais de Cátion TRPV/antagonistas & inibidores , Tiazóis/farmacologia , Analgésicos/química , Animais , Compostos Azabicíclicos/química , Cobaias , Humanos , Microssomos/efeitos dos fármacos , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Tiazóis/química
12.
J Pharmacol Sci ; 133(1): 9-17, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28034513

RESUMO

We investigated the mechanisms underlying the suppression of the rewarding effects of opioids using the femur bone cancer (FBC) mouse model. The rewarding and antinociceptive effects of subcutaneously administered morphine and oxycodone in the FBC model mice were assessed using the conditioned place preference test and the von-Frey test. In FBC mice, antinociceptive doses of morphine (30 mg/kg) and oxycodone (5 mg/kg) did not produce the rewarding effects but excessive doses of morphine (300 mg/kg) and oxycodone (100 mg/kg) did. Western blot analyses revealed a transient and significant increase in phosphorylated-extracellular regulated kinase (p-ERK) levels in ventral tegmental area (VTA) 5 min after the administration of morphine in sham-group. Interestingly, in FBC group, a regular dose of morphine did not increase p-ERK levels but a high dose of morphine caused an increase in p-ERK level 5 min after administration. The rewarding effects of a regular dose of and a high dose of morphine in the sham-operation and FBC model, respectively, were significantly inhibited by the MEK inhibitor. The suppression of p-ERK might result in resistance to these rewarding effects under the conditions of bone cancer.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Morfina/farmacologia , Oxicodona/farmacologia , Receptores Opioides mu/agonistas , Recompensa , Regulação para Cima/efeitos dos fármacos , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/enzimologia , Analgésicos/farmacologia , Animais , Butadienos/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Camundongos , Morfina/antagonistas & inibidores , Nitrilas/farmacologia , Oxicodona/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Ensaio Radioligante , Receptores Opioides mu/metabolismo
13.
Bioorg Med Chem Lett ; 26(20): 4936-4941, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27634196

RESUMO

A series of 2',4'-dimethyl-[4,5'-bithiazol]-2-yl amino derivatives have been identified as selective TRPV4 antagonists that display inhibition potencies against 4α-phorbol 12,13-didecanoate (4αPDD), well known as a TRPV4 selective agonist and/or a hypotonicity. In particular, 9-(6-((2',4'-dimethyl-[4,5'-bithiazol]-2-yl)amino)nicotinoyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one showed an analgesic effect in Freund's Complete Adjuvant (FCA) induced mechanical hyperalgesia model in guinea pig (reported in Part 1). However, there are some concerns such as species differences and the need for higher plasma exposure to achieve target efficacy for evaluation by an in vivo pain model. In this Letter, we report the resolution of some of the problems by further optimizing the chemical scaffold.


Assuntos
Canais de Cátion TRPV/antagonistas & inibidores , Tiazóis/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Cricetinae , Descoberta de Drogas , Relação Estrutura-Atividade , Tiazóis/administração & dosagem , Tiazóis/química , Tiazóis/farmacocinética
14.
Bioorg Med Chem Lett ; 26(20): 4930-4935, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27637151

RESUMO

A novel series of 2',4'-dimethyl-[4,5'-bithiazol]-2-yl amino derivatives were found by high throughput screening of the TRPV4 receptor, at which these compounds showed competitive antagonist potential against 4α-phorbol 12,13-didecanoate (4αPDD) as the selective TRPV4 agonist and showed excellent selectivity for TRPV1, N-type and L-type calcium ion channels, but poor ADME profile. In our SAR strategy, we found that the lead molecule 1 also having the unique 3-oxa-9-azabicyclo [3.3.1] nonan-7-one on the right part showed potent TRPV4 antagonist activity, good solubility at pH 6.8, good microsomal stability for human and better ADME profile including oral bioavailability. Moreover, compound 1 had an analgesic effect in Freund's Complete Adjuvant (FCA) induced mechanical hyperalgesia model in guinea pig. In this letter, we report a lead optimization process to identify the lead compound 1 (Fig. 1).


Assuntos
Analgésicos/uso terapêutico , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/farmacocinética , Animais , Disponibilidade Biológica , Descoberta de Drogas , Humanos , Relação Estrutura-Atividade , Canais de Cátion TRPV/antagonistas & inibidores
15.
Eur J Pharmacol ; 773: 1-12, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26802873

RESUMO

Although estrous cycle has been reported to influence antiociceptive effect of morphine in several pain conditions, its effect on cancer pain is not well established. We investigated the effect of estrogen on morphine antinociception using a bone cancer pain model and compared its potency with that of oxycodone. Female mice were ovariectomized (OVX) for preparation of a femur bone cancer pain (FBC) model. ß-estradiol was subcutaneously (s.c.) administered and antinociceptive effects of opioids was assessed using the von Frey monofilament test. Although morphine (5-20mg/kg, s.c.) did have significant antinociceptive effects in the FBC-OVX group, its effects in the FBC-OVX+ß-estradiol (OVX+E) group was limited. Oxycodone (1-5mg/kg, s.c.) exhibited significant effects in both groups. Expression changes in opioid-related genes (µ-, κ-, δ-opioid receptors, prodynorphin, proenkephalin, proopiomelanocortin) in the spinal and supraspinal sites were examined among the sham-OVX, sham-OVX+E, FBC-OVX, and FBC-OVX+E groups by in situ hybridization. These studies detected a significant increase in prodynorphin in the spinal dorsal horn of the FBC-OVX+E group. Spinal injection of a dynorphin-A antibody to FBC-OVX+E mice restored antinociception of morphine. In conclusion, we detected a differential effect of estrogen on morphine- and oxycodone-induced antinociception in a female FBC model. The effect of morphine was limited with estrogen exposure, which may be due to estrogen- and pain-mediated spinal expression of dynorphin-A.


Assuntos
Neoplasias Ósseas/complicações , Estrogênios/farmacologia , Fêmur/efeitos dos fármacos , Morfina/farmacologia , Oxicodona/farmacologia , Dor/complicações , Dor/tratamento farmacológico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Linhagem Celular Tumoral , Dinorfinas/genética , Ciclo Estral/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Morfina/uso terapêutico , Ovariectomia , Oxicodona/uso terapêutico , Dor/genética , Dor/fisiopatologia
16.
Eur J Neurosci ; 42(5): 2135-43, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26036915

RESUMO

The CA1-projecting axons of CA3 pyramidal cells, called Schaffer collaterals, constitute one of the major information flow routes in the hippocampal formation. Recent anatomical studies have revealed the non-random structural connectivity between CA3 and CA1, but little is known regarding the functional connectivity (i.e. how CA3 network activity is functionally transmitted downstream to the CA1 network). Using functional multi-neuron calcium imaging of rat hippocampal slices, we monitored the spatiotemporal patterns of spontaneous CA3 and CA1 burst activity under pharmacological GABAergic blockade. We found that spatially clustered CA3 activity patterns were transformed into layered CA1 activity sequences. Specifically, synchronized bursts initiated from multiple hot spots in CA3 ensembles, and CA1 neurons located deeper in the pyramidal cell layer were recruited during earlier phases of the burst events. The order of these sequential activations was maintained across the bursts, but the sequence velocity varied depending on the inter-burst intervals. Thus, CA3 axons innervate CA1 neurons in a highly topographical fashion.


Assuntos
Potenciais de Ação/fisiologia , Região CA1 Hipocampal/fisiologia , Região CA3 Hipocampal/fisiologia , Neurônios/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA3 Hipocampal/citologia , Região CA3 Hipocampal/efeitos dos fármacos , Cálcio/metabolismo , Vias Neurais/citologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos Wistar , Técnicas de Cultura de Tecidos , Imagens com Corantes Sensíveis à Voltagem
17.
Eur J Neurosci ; 42(2): 1818-29, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25967117

RESUMO

Epilepsy is a chronic brain disease characterised by recurrent seizures. Many studies of this disease have focused on local neuronal activity, such as local field potentials in the brain. In addition, several recent studies have elucidated the collective behavior of individual neurons in a neuronal network that emits epileptic activity. However, little is known about the effects of antiepileptic drugs on neuronal networks during seizure-like events (SLEs) at single-cell resolution. Using functional multineuron Ca(2+) imaging (fMCI), we monitored the activities of multiple neurons in the rat hippocampal CA1 region on treatment with the proconvulsant bicuculline under Mg(2+) -free conditions. Bicuculline induced recurrent synchronous Ca(2+) influx, and the events were correlated with SLEs. Other proconvulsants, such as 4-aminopyridine, pentetrazol, and pilocarpine, also induced synchronous Ca(2+) influx. We found that the antiepileptic drugs phenytoin, flupirtine, and ethosuximide, which have different mechanisms of action, exerted heterogeneous effects on bicuculline-induced synchronous Ca(2+) influx. Phenytoin and flupirtine significantly decreased the peak, the amount of Ca(2+) influx and the duration of synchronous events in parallel with the duration of SLEs, whereas they did not abolish the synchronous events themselves. Ethosuximide increased the duration of synchronous Ca(2+) influx and SLEs. Furthermore, the magnitude of the inhibitory effect of phenytoin on the peak synchronous Ca(2+) influx level differed according to the peak amplitude of the synchronous event in each individual cell. Evaluation of the collective behavior of individual neurons by fMCI seems to be a powerful tool for elucidating the profiles of antiepileptic drugs.


Assuntos
Anticonvulsivantes/farmacologia , Cálcio/metabolismo , Epilepsia/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Neurônios/metabolismo , 4-Aminopiridina/farmacologia , Animais , Animais Recém-Nascidos , Bicuculina/toxicidade , Convulsivantes/toxicidade , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Epilepsia/metabolismo , Epilepsia/patologia , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/fisiologia , Feminino , Técnicas In Vitro , Masculino , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio/farmacologia , Ratos , Ratos Wistar , Estatísticas não Paramétricas
18.
Br J Pharmacol ; 172(8): 2148-64, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25521524

RESUMO

BACKGROUND AND PURPOSE: We demonstrated previously that oxycodone has potent antinociceptive effects at supraspinal sites. In this study, we investigated changes in neuronal function and antinociceptive mechanisms of oxycodone at ventrolateral periaqueductal gray (VLPAG) neurons, which are a major site of opioid action, in a femur bone cancer (FBC) model with bone cancer-related pain. EXPERIMENTAL APPROACH: We characterized the supraspinal antinociceptive profiles of oxycodone and morphine on mechanical hypersensitivity in the FBC model. Based on the disinhibition mechanism underlying supraspinal opioid antinociception, the effects of oxycodone and morphine on GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in VLPAG neurons were evaluated in slices from the FBC model. KEY RESULTS: The supraspinal antinociceptive effects of oxycodone, but not morphine, were abolished by blocking G protein-gated inwardly rectifying potassium1 (Kir 3.1) channels. In slices from the FBC model, GABAergic synaptic transmission at VLPAG neurons was enhanced, as indicated by a leftward shift of the input-output relationship curve of evoked IPSCs, the increased paired-pulse facilitation and the enhancement of miniature IPSC frequency. Following treatment with oxycodone and morphine, IPSCs were reduced in the FBC model, and the inhibition of presynaptic GABA release by oxycodone, but not morphine was enhanced and dependent on Kir 3.1 channels. CONCLUSION AND IMPLICATIONS: Our results demonstrate that Kir 3.1 channels are important for supraspinal antinociception and presynaptic GABA release inhibition by oxycodone in the FBC model. Enhanced GABAergic synaptic transmission at VLPAG neurons in the FBC model is an important site of supraspinal antinociception by oxycodone via Kir 3.1 channel activation.


Assuntos
Analgésicos Opioides/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/fisiologia , Neurônios/efeitos dos fármacos , Oxicodona/farmacologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Ácido gama-Aminobutírico/fisiologia , Analgésicos Opioides/uso terapêutico , Animais , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/fisiopatologia , Linhagem Celular Tumoral , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/antagonistas & inibidores , Hiperalgesia/tratamento farmacológico , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C3H , Morfina/farmacologia , Morfina/uso terapêutico , Neurônios/fisiologia , Oxicodona/uso terapêutico , Dor/tratamento farmacológico , Dor/fisiopatologia , Substância Cinzenta Periaquedutal/fisiologia , Transmissão Sináptica/efeitos dos fármacos
19.
J Pharmacol Sci ; 126(3): 264-73, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25346041

RESUMO

Oxaliplatin is a chemotherapeutic agent that induces chronic refractory neuropathy. To determine whether opioids effectively relieve this chronic neuropathy, we investigated the efficacies of morphine, oxycodone, and fentanyl, and the mechanisms underlying opioid antinociception, in oxaliplatin-induced neuropathy in rats. Rats exhibited significant mechanical allodynia following 2 weeks of chronic oxaliplatin administration. Within the range of doses that did not induce sedation and/or muscle rigidity, morphine (3 mg/kg, subcutaneously, s.c.) and oxycodone (0.3-0.56 mg/kg, s.c.) completely reversed oxaliplatin-induced mechanical allodynia, whereas fentanyl (0.017-0.03 mg/kg, s.c.) showed partial antinociception. The antinociception of the optimal doses of morphine and oxycodone were completely inhibited by pertussis toxin (PTX; 0.5 µg/rat, i.c.v.), a Gi/o protein inhibitor, while the partial effect of fentanyl was not affected in the oxaliplatin model. In the [(35)S]-GTPγS binding assay, activation of µ-opioid receptor by fentanyl, but not by morphine or oxycodone, in the mediodorsal thalamus was significantly reduced in oxaliplatin-treated rats. These results indicate that the lower antinociceptive potency of fentanyl in the oxaliplatin model might in part result from the loss of PTX-sensitive Gi/o protein activation, and the degree of Gi/o protein activation might be related to the potency of antinociception by opioids in this model.


Assuntos
Analgésicos Opioides/farmacologia , Analgésicos/farmacologia , Fentanila/farmacologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Hiperalgesia/tratamento farmacológico , Morfina/farmacologia , Nociceptividade/efeitos dos fármacos , Compostos Organoplatínicos , Oxicodona/farmacologia , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/antagonistas & inibidores , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Masculino , Núcleo Mediodorsal do Tálamo/efeitos dos fármacos , Núcleo Mediodorsal do Tálamo/metabolismo , Oxaliplatina , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/fisiopatologia , Toxina Pertussis/farmacologia , Ratos Sprague-Dawley , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
20.
J Pharmacol Sci ; 126(1): 47-55, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25141998

RESUMO

The rewarding effects of µ-receptor agonists can be suppressed under several pain conditions. We recently showed that clinically used µ-receptor agonists possess efficacies for relieving the neuropathic pain induced by chemotherapeutic drug in rats; however, it is possible that the use of µ-receptor agonists may trigger the rewarding effects even under chemotherapeutic drug-induced neuropathic pain. Nevertheless, no information is available regarding whether µ-receptor agonists produce psychological dependence under chemotherapeutic drug-induced neuropathic pain. Therefore, we examined the effects of neuropathy induced by chemotherapeutic drugs on the rewarding effects of morphine, oxycodone, and fentanyl in rats. Repeated treatment with oxaliplatin or paclitaxel produced neuropathy as measured by the von Frey test. Rewarding effects produced by antinociceptive doses of µ-receptor agonists were not suppressed under oxaliplatin- or paclitaxel-induced neuropathy. Furthermore, the morphine-induced increase in the release of dopamine from the nucleus accumbens, which is a critical step in the rewarding effects of µ-receptor agonists, was not altered in paclitaxel-treated rats. These results suggest that the rewarding effects of µ-receptor agonists can still be established under oxaliplatin- or paclitaxel-induced neuropathic pain. Therefore, patients should be carefully monitored for psychological dependence on µ-receptor agonists when they are used to control chemotherapeutic drug-induced neuropathic pain.


Assuntos
Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos/efeitos adversos , Fentanila/farmacologia , Fentanila/uso terapêutico , Morfina/farmacologia , Morfina/uso terapêutico , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Compostos Organoplatínicos/efeitos adversos , Oxicodona/farmacologia , Oxicodona/uso terapêutico , Paclitaxel/efeitos adversos , Receptores Opioides mu/agonistas , Animais , Fentanila/efeitos adversos , Masculino , Morfina/efeitos adversos , Oxaliplatina , Oxicodona/efeitos adversos , Ratos Sprague-Dawley , Transtornos Relacionados ao Uso de Substâncias/etiologia
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