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1.
J Med Chem ; 62(7): 3228-3250, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30893553

RESUMO

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.

2.
PLoS One ; 12(7): e0181782, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28742141

RESUMO

Bruton's tyrosine kinase (BTK) regulates critical signal transduction pathways involved in the pathobiology of rheumatoid arthritis (RA) and other autoimmune disorders. BMS-986142 is a potent and highly selective reversible small molecule inhibitor of BTK currently being investigated in clinical trials for the treatment of both RA and primary Sjögren's syndrome. In the present report, we detail the in vitro and in vivo pharmacology of BMS-986142 and show this agent provides potent and selective inhibition of BTK (IC50 = 0.5 nM), blocks antigen receptor-dependent signaling and functional endpoints (cytokine production, co-stimulatory molecule expression, and proliferation) in human B cells (IC50 ≤ 5 nM), inhibits Fcγ receptor-dependent cytokine production from peripheral blood mononuclear cells, and blocks RANK-L-induced osteoclastogenesis. Through the benefits of impacting these important drivers of autoimmunity, BMS-986142 demonstrated robust efficacy in murine models of rheumatoid arthritis (RA), including collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA). In both models, robust efficacy was observed without continuous, complete inhibition of BTK. When a suboptimal dose of BMS-986142 was combined with other agents representing the current standard of care for RA (e.g., methotrexate, the TNFα antagonist etanercept, or the murine form of CTLA4-Ig) in the CIA model, improved efficacy compared to either agent alone was observed. The results suggest BMS-986142 represents a potential therapeutic for clinical investigation in RA, as monotherapy or co-administered with agents with complementary mechanisms of action.


Assuntos
Artrite Experimental/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia , Animais , Formação de Anticorpos/efeitos dos fármacos , Artrite Experimental/imunologia , Artrite Experimental/patologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/patologia , Camundongos Endogâmicos BALB C , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteoclastos/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/imunologia , Ligante RANK/imunologia
3.
J Med Chem ; 59(19): 9173-9200, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27583770

RESUMO

Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clinical studies.


Assuntos
Carbazóis/química , Carbazóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia , Animais , Carbazóis/farmacocinética , Cristalografia por Raios X , Feminino , Humanos , Isomerismo , Macaca fascicularis , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/metabolismo , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Relação Estrutura-Atividade
4.
Psychopharmacology (Berl) ; 218(4): 635-47, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21643676

RESUMO

RATIONALE: α7 nicotinic acetylcholine receptor (nAChR) agonists are proposed as candidate agents for the adjunctive treatment of cognitive deficits associated with schizophrenia. Despite the pursuit of such an approach clinically, it is surprising that the preclinical profile of pro-cognitive agents in conjunction with antipsychotic drugs is currently unexplored. OBJECTIVES: We determined if the memory-enhancing effects of the selective α7 nAChR agonist WYE-103914 were preserved in the presence of the atypical antipsychotic drug risperidone, and if the antipsychotic-like profile of risperidone was preserved in the presence of WYE-103914. METHODS: Using the rat novel object recognition (NOR) paradigm, the maintenance of memory-enhancing activity of the α7 nAChR agonist WYE-103914 in the presence of risperidone was examined. Similarly, in the standard tests of antipsychotic-like activity, apomorphine-induced climbing (AIC) in mice and conditioned avoidance responding (CAR) in rats, the preservation of antipsychotic-like activity of risperidone was evaluated in the presence of WYE-103914. RESULTS: WYE-103914 exhibited memory-enhancing activity in rat NOR, and this effect of WYE-103914 was retained in the presence of risperidone. In AIC, the atypical antipsychotic profile of risperidone was not significantly altered by WYE-103914. In contrast, WYE-103914 moderately potentiated the efficacy profile of risperidone in CAR, an effect that did not appear to be convincingly linked to a pharmacokinetic interaction. CONCLUSIONS: These data underscore the value of a preclinical evaluation of the adjunctive profile of a memory-enhancing agent in combination with antipsychotics and provide further support to augmentation with α7 nAChR agonists to address the cognitive deficits associated with schizophrenia.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Piridinas/farmacologia , Risperidona/farmacologia , Esquizofrenia/tratamento farmacológico , Ureia/análogos & derivados , Animais , Antipsicóticos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Avaliação Pré-Clínica de Medicamentos , Interações de Medicamentos , Quimioterapia Combinada , Masculino , Memória/efeitos dos fármacos , Camundongos , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Receptores Nicotínicos/efeitos dos fármacos , Receptores Nicotínicos/metabolismo , Esquizofrenia/fisiopatologia , Ureia/farmacologia , Receptor Nicotínico de Acetilcolina alfa7
5.
J Med Chem ; 53(10): 4066-84, 2010 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-20443629

RESUMO

As part of an effort to identify 5-HT(1A) antagonists that did not possess typical arylalkylamine or keto/amido-alkyl aryl piperazine scaffolds, prototype compound 10a was identified from earlier work in a combined 5-HT(1A) antagonist/SSRI program. This quinolyl-piperazinyl piperidine analogue displayed potent, selective 5-HT(1A) antagonism but suffered from poor oxidative metabolic stability, resulting in low exposure following oral administration. SAR studies, driven primarily by in vitro liver microsomal stability assessment, identified compound 10b, which displayed improved oral bioavailability and lower intrinsic clearance. Further changes to the scaffold (e.g., 10r) resulted in a loss in potency. Compound 10b displayed cognitive enhancing effects in a number of animal models of learning and memory, enhanced the antidepressant-like effects of the SSRI fluoxetine, and reversed the sexual dysfunction induced by chronic fluoxetine treatment.


Assuntos
Piperazinas/síntese química , Piperidinas/síntese química , Quinolinas/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina , Acetilcolina/metabolismo , Administração Oral , Precursor de Proteína beta-Amiloide/genética , Animais , Antidepressivos/síntese química , Antidepressivos/química , Antidepressivos/farmacologia , Disponibilidade Biológica , Células CHO , Córtex Cerebral/metabolismo , Cognição/efeitos dos fármacos , Cricetinae , Cricetulus , Fluoxetina/farmacologia , Hipocampo/metabolismo , Técnicas In Vitro , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Microssomos Hepáticos/metabolismo , Nootrópicos/síntese química , Nootrópicos/química , Nootrópicos/farmacologia , Ereção Peniana/efeitos dos fármacos , Piperazinas/química , Piperazinas/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Ratos , Serotonina/metabolismo , Relação Estrutura-Atividade
6.
Int J Neuropsychopharmacol ; 13(9): 1193-205, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20047711

RESUMO

Biogenic amines such as norepinephrine, dopamine, and serotonin play a well-described role in the treatment of mood disorders and some types of pain. As alpha2A-adrenoceptors regulate the release of these neurotransmitters, we examined the therapeutic potential of BRL 44408, a potent (Ki=8.5 nM) and selective (>50-fold) alpha2A-adrenoceptor antagonist (K(B)=7.9 nM). In rats, BRL 44408 penetrated the central nervous system resulting in peak brain and plasma concentrations of 586 ng/g and 1124 ng/ml, respectively. In a pharmacodynamic assay, pretreatment with BRL 44408 to rats responding under a fixed-ratio 30 operant response paradigm resulted in a rightward shift of the clonidine dose-response curve, an effect indicative of alpha2-adrenoceptor antagonism in vivo. Consistent with presynaptic autoreceptor antagonism and tonic regulation of neurotransmitter release, acute administration of BRL 44408 elevated extracellular concentrations of norepinephrine and dopamine, but not serotonin, in the medial prefrontal cortex. Additionally, BRL 44408, probably by inhibiting alpha2A heteroceptors, produced a significant increase in cortical levels of acetylcholine. In the forced swim test and schedule-induced polydipsia assay, BRL 44408 produced an antidepressant-like response by dose-dependently decreasing immobility time and adjunctive water intake, respectively, while in a model of visceral pain, BRL 44408 exhibited analgesic activity by decreasing para-phenylquinone (PPQ)-induced abdominal stretching. Finally, BRL 44408 did not produce deficits in overall motor coordination nor alter general locomotor activity. This preclinical characterization of the neurochemical and behavioural profile of BRL 44408 suggests that selective antagonism of alpha2A-adrenoceptors may represent an effective treatment strategy for mood disorders and visceral pain.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Analgésicos/farmacologia , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Imidazóis/farmacologia , Isoindóis/farmacologia , Receptores Adrenérgicos alfa 2/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/farmacocinética , Analgésicos/farmacocinética , Animais , Antidepressivos/farmacocinética , Monoaminas Biogênicas/metabolismo , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Imidazóis/farmacocinética , Isoindóis/farmacocinética , Masculino , Camundongos , Microdiálise , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Natação , Sede/efeitos dos fármacos
7.
Neuropharmacology ; 58(1): 69-77, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19615387

RESUMO

The widely reported effects of oxytocin (OT) on CNS function has generated considerable interest in the therapeutic potential for targeting this system for a variety of human psychiatric diseases, including anxiety disorders, autism, schizophrenia, and depression. The utility of synthetic OT, as both a research tool and neurotherapeutic, is limited by the physiochemical properties inherent in most neuropeptides, notably its short half-life and poor blood brain barrier penetration. Subsequently, the discovery and development of non-peptide molecules that act as selective agonists of the oxytocin receptor (OTR) has been an important goal of the field. In this study, we report the receptor and behavioral pharmacology of WAY-267464, a first generation small-molecule OTR agonist. WAY-267464 is a high-affinity, potent, and selective (vs. V1a, V2, V1b) agonist of the OTR. In assays measuring both behavioral (four-plate test, elevated zero maze) and autonomic (stress-induced hyperthermia) parameters of the anxiety response, WAY-267464 exhibits an anxiolytic-like profile similar to OT. We have demonstrated that the anxiolytic-like profile of WAY-267464 is mediated through central sites of action. WAY-267464 also significantly reverses disruption in prepulse inhibition of the acoustic startle reflex induced by either MK-801 or amphetamine, similar to the antipsychotic-like effects previously reported for OT. Interestingly, in the mouse tail suspension test, WAY-267464 failed to produce changes in immobility that are seen with OT, raising the question of whether the antidepressant-like activity of OT may be working independently of the OTR. A selective OTR antagonist also failed to block the effects of OT on immobility in the TST. The significance of these findings for shaping the clinical development of OTR agonists is discussed.


Assuntos
Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Ocitocina/farmacologia , Receptores de Ocitocina/agonistas , Estimulação Acústica/efeitos adversos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Benzodiazepinas/farmacologia , Benzodiazepinas/uso terapêutico , Células CHO , Cricetinae , Cricetulus , Febre/tratamento farmacológico , Febre/etiologia , Elevação dos Membros Posteriores/métodos , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Inibição Neural/efeitos dos fármacos , Ocitocina/agonistas , Ligação Proteica/efeitos dos fármacos , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Estresse Psicológico/complicações
8.
J Pharmacol Exp Ther ; 332(1): 190-201, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19828876

RESUMO

The preclinical characterization of WS-50030 [7-{4-[3-(1H-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one] is described. In vitro binding and functional studies revealed highest affinity to the D(2) receptor (D(2L) K(i), 4.0 nM) and serotonin transporter (K(i), 7.1 nM), potent D(2) partial agonist activity (EC(50), 0.38 nM; E(max), 30%), and complete block of the serotonin transporter (IC(50), 56.4 nM). Consistent with this in vitro profile, WS-50030 (10 mg/kg/day, 21 days) significantly increased extracellular 5-HT in the rat medial prefrontal cortex, short-term WS-50030 treatment blocked apomorphine-induced climbing (ID(50), 0.51 mg/kg) in a dose range that produced minimal catalepsy in mice and induced low levels of contralateral rotation in rats with unilateral substantia nigra 6-hydroxydopamine lesions (10 mg/kg i.p.), a behavioral profile similar to that of the D(2) partial agonist aripiprazole. In a rat model predictive of antipsychotic-like activity, WS-50030 and aripiprazole reduced conditioned avoidance responding by 42 and 55% at 10 mg/kg, respectively. Despite aripiprazole's reported lack of effect on serotonin transporters, long-term treatment with aripiprazole or WS-50030 reversed olfactory bulbectomy-induced hyperactivity at doses that did not reduce activity in sham-operated rats, indicating antidepressant-like activity for both compounds. Despite possessing serotonin reuptake inhibitory activity in addition to D(2) receptor partial agonism, WS-50030 displays activity in preclinical models predictive of antipsychotic- and antidepressant efficacy similar to aripiprazole, suggesting potential efficacy of WS-50030 versus positive and negative symptoms of schizophrenia, comorbid mood symptoms, bipolar disorder, major depressive disorder, and treatment-resistant depression. Furthermore, WS-50030 provides a tool to further explore how combining these mechanisms might differentiate from other antipsychotics or antidepressants.


Assuntos
Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Benzoxazóis/farmacologia , Agonistas de Dopamina/farmacologia , Indenos/farmacologia , Receptores de Dopamina D2/agonistas , Inibidores de Captação de Serotonina/farmacologia , Animais , Antidepressivos/química , Antipsicóticos/química , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Benzoxazóis/química , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Dopamina/metabolismo , Agonistas de Dopamina/química , Avaliação Pré-Clínica de Medicamentos , Humanos , Indenos/química , Masculino , Camundongos , Camundongos Endogâmicos , Microdiálise , Atividade Motora/efeitos dos fármacos , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Serotonina/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas do Receptor 5-HT2 de Serotonina , Inibidores de Captação de Serotonina/química , Transfecção
9.
Int J Neuropsychopharmacol ; 12(8): 1045-53, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19435548

RESUMO

Sexual dysfunction associated with antidepressant treatment continues to be a major compliance issue for antidepressant therapies. 5-HT(1A) antagonists have been suggested as beneficial adjunctive treatment in respect of antidepressant efficacy; however, the effects of 5-HT(1A) antagonism on antidepressant-induced side-effects has not been fully examined. The present study was conducted to evaluate the ability of acute or chronic treatment with 5-HT(1A) antagonists to alter chronic fluoxetine-induced impairments in sexual function. Chronic 14-d treatment with fluoxetine resulted in a marked reduction in the number of non-contact penile erections in sexually experienced male rats, relative to vehicle-treated controls. Acute administration of the 5-HT(1A) antagonist WAY-101405 resulted in a complete reversal of chronic fluoxetine-induced deficits on non-contact penile erections at doses that did not significantly alter baselines. Chronic co-administration of the 5-HT(1A) antagonists WAY-100635 or WAY-101405 with fluoxetine prevented fluoxetine-induced deficits in non-contact penile erections in sexually experienced male rats. Moreover, withdrawal of WAY-100635 from co-treatment with chonic fluoxetine, resulted in a time-dependent reinstatement of chronic fluoxetine-induced deficits in non-contact penile erections. Additionally, chronic administration of SSA-426, a molecule with dual activity as both a SSRI and 5-HT(1A) antagonist, did not produce deficits in non-contact penile erections at doses demonstrated to have antidepressant-like activity in the olfactory bulbectomy model. Taken together, these data suggest that 5-HT(1A) antagonist treatment may have utility for the management of SSRI-induced sexual dysfunction.


Assuntos
Fluoxetina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina , Inibidores de Captação de Serotonina/farmacologia , Disfunções Sexuais Fisiológicas/induzido quimicamente , Disfunções Sexuais Fisiológicas/prevenção & controle , Aminopiridinas/farmacologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Comportamento Exploratório/efeitos dos fármacos , Feminino , Masculino , Bulbo Olfatório/lesões , Bulbo Olfatório/fisiologia , Ovariectomia , Piperazinas/farmacologia , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Fatores de Tempo
10.
J Pharmacol Exp Ther ; 327(3): 827-39, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18753411

RESUMO

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) enhance N-methyl-d-aspartate receptor function and may represent a novel approach for the treatment of schizophrenia. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone], a recently identified potent and selective mGlu5 PAM, increased (9-fold) the response to threshold concentration of glutamate (50 nM) in fluorometric Ca(2+) assays (EC(50) = 170 nM) in human embryonic kidney 293 cells expressing rat mGlu5. In the same system, ADX47273 dose-dependently shifted mGlu5 receptor glutamate response curve to the left (9-fold at 1 microM) and competed for binding of [(3)H]2-methyl-6-(phenylethynyl)pyridine (K(i) = 4.3 microM), but not [(3)H]quisqualate. In vivo, ADX47273 increased extracellular signal-regulated kinase and cAMP-responsive element-binding protein phosphorylation in hippocampus and prefrontal cortex, both of which are critical for glutamate-mediated signal transduction mechanisms. In models sensitive to antipsychotic drug treatment, ADX47273 reduced rat-conditioned avoidance responding [minimal effective dose (MED) = 30 mg/kg i.p.] and decreased mouse apomorphine-induced climbing (MED = 100 mg/kg i.p.), with little effect on stereotypy or catalepsy. Furthermore, ADX47273 blocked phencyclidine, apomorphine, and amphetamine-induced locomotor activities (MED = 100 mg/kg i.p.) in mice and decreased extracellular levels of dopamine in the nucleus accumbens, but not in the striatum, in rats. In cognition models, ADX47273 increased novel object recognition (MED = 1 mg/kg i.p.) and reduced impulsivity in the five-choice serial reaction time test (MED = 10 mg/kg i.p.) in rats. Taken together, these effects are consistent with the hypothesis that allosteric potentiation of mGlu5 may provide a novel approach for development of antipsychotic and procognitive agents.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Antipsicóticos/farmacologia , Cognição/efeitos dos fármacos , Oxidiazóis/farmacologia , Piperidinas/farmacologia , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Hipocampo/metabolismo , Humanos , Córtex Pré-Frontal/metabolismo , Ratos , Receptor de Glutamato Metabotrópico 5
11.
Neuropharmacology ; 54(7): 1136-42, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18423777

RESUMO

Recent studies have reported that estrogen has antidepressant-like effects in animal models. In this study we used the highly selective ER beta agonist, WAY-200070, to examine the role of ER beta activation on brain neurochemistry and activity in antidepressant and anxiolytic models in male mice. Within 15 min of administration, WAY-200070 (30 mg/kg s.c.) caused the nuclear translocation of striatal ER beta receptors from the cytosol. WAY-200070 also increased c-fos activation 4h, but not 15 min after administration. Both nuclear translocation and c-fos induction effects of WAY-200070 demonstrate that WAY-200070 has bound to estrogen receptors and triggered downstream events. The absence of these effects in the ER beta KO mice confirms that WAY-200070 was targeting ER beta. Administration of WAY-200070 (30 mg/kg s.c.) produced a delayed approximately 50% increase in dopamine in the striatum of wild type mice. The effect was significant and maintained from 90 to 240 min. This increase was absent in ER beta KO mice. In wild type mice, WAY-200070 (30 mg/kg s.c.) also produced a delayed and transient approximately 100% increase in 5-HT. To further investigate the role of ER beta receptors on serotonergic function, 5-HTP accumulation was measured. ER beta KO mice were found to have reduced frontal cortex levels of 5-HTP, indicating reduced tryptophan hydroxylase activity. WAY-200070 (3-30 mg/kg s.c.) was also tested in behavioural models. WAY-200070 (30 mg/kg s.c.) reduced immobility time in the mouse tail suspension test indicating an antidepressant-like effect. WAY-200070 (30 mg/kg) showed anxiolytic-like effects in the four-plate test (increased punished crossings) and stress-induced hyperthermia (attenuation of hyperthermic response). The effects of the selective ER beta agonist, WAY-200070, on dopamine and serotonin, the anxiolytic-like and antidepressant-like effects as well as the genotype specific effects on neurochemistry support that positive modulation of ER beta function may provide a novel treatment for affective disorders.


Assuntos
Ansiolíticos/uso terapêutico , Antidepressivos/uso terapêutico , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Receptor beta de Estrogênio/agonistas , Oxazóis/uso terapêutico , Fenóis/uso terapêutico , 5-Hidroxitriptofano/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Receptor alfa de Estrogênio/deficiência , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/deficiência , Receptor beta de Estrogênio/metabolismo , Elevação dos Membros Posteriores/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microdiálise , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Desempenho Psicomotor/efeitos dos fármacos , Fatores de Tempo
12.
J Pharmacol Exp Ther ; 308(1): 214-20, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14566007

RESUMO

Chronic relapsing/remitting experimental autoimmune encephalomyelitis (EAE) can be induced in 8-week-old female SJL/J(H-2) mice via inoculation with the p139-151 peptide of myelin proteolipid protein (PLP), Mycobacterium tuberculosis (MT), complete Freund's adjuvant (CFA), and Bordatella pertussis. EAE is a relevant preclinical model of MS that incorporates several aspects of the clinical disease. Chief among these are the inflammatory mediated neurological deficits. While the impact of localized spinal cord demyelination on neurotransmission has been modeled successfully, relatively little work has been done with spinal cord from animals with EAE. The goal of this study was to assess the utility of a grease-gap tissue bath methodology in the detection of transmission deficits in EAE spinal cord tissue. Spinal cords removed from EAE mice at different phases of the neurological deficit were assessed for their response to both lumbar and sacral application of one of several depolarizing agents (veratridine, potassium chloride [KCl], (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA]). The main finding of this study is that transmission deficits were detected in EAE mice at the onset of the neurological deficits. They were sustained for a period of approximately 2 to 3 weeks post disease onset followed by a gradual recovery of group function. The other finding is that there is a decrease in the latency to achieve AMPA-mediated depolarization in sacral spinal cord that is independent of the magnitude of the depolarization response. These results suggest that this methodology can be utilized to assess sensory and motor deficits in spinal cord from EAE animals.


Assuntos
Encefalomielite Autoimune Experimental/fisiopatologia , Transmissão Sináptica , Fatores Etários , Animais , Modelos Animais de Doenças , Eletrofisiologia , Feminino , Camundongos , Cloreto de Potássio/farmacologia , Medula Espinal/fisiopatologia , Veratridina/farmacologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia
13.
J Biopharm Stat ; 13(1): 141-58, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12635908

RESUMO

Experimental autoimmune encephalomyelitis (EAE) is a procedure used in the laboratory to examine drugs that may have utility in treating multiple sclerosis (MS). The problem of modeling the disease curve in animals with EAE is studied. The classification of animals after each experiment is considered and the chi-square test is proposed to test a homogeneity between treatment groups. A mixture type of nonlinear mixed-effects model with repeated measurements is considered, assuming that the onset and/or remission of disease is the fixed effect as well as the random effect. Statistical inference on the parameters of the disease curves is discussed. The proposed model is shown to be efficient for comparing the disease curves with different treatments. Examples concerning the study of the effects of test compounds in EAE are presented to illustrate the proposed model and statistical methodologies.


Assuntos
Tratamento Farmacológico/estatística & dados numéricos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Modelos Estatísticos , Animais , Interpretação Estatística de Dados , Tratamento Farmacológico/métodos , Camundongos
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