RESUMO
Kv3.1 and Kv3.2 voltage-gated potassium channels are expressed on parvalbumin-positive GABAergic interneurons in corticolimbic brain regions and contribute to high-frequency neural firing. The channels are also expressed on GABAergic neurons of the basal ganglia, substantia nigra, and ventral tegmental area (VTA) where they regulate firing patterns critical for movement control, reward, and motivation. Modulation of Kv3.1 and Kv3.2 channels may therefore have potential in the treatment of disorders in which these systems have been implicated, such as bipolar disorder. Following the recent development of a potassium channel modulator, AUT1-an imidazolidinedione compound that specifically increases currents mediated by Kv3.1 and Kv3.2 channels in recombinant systems-we report that the compound is able to reverse 'manic-like' behavior in two mouse models: amphetamine-induced hyperactivity and ClockΔ19 mutants. AUT1 completely prevented amphetamine-induced hyperactivity in a dose-dependent manner, similar to the atypical antipsychotic, clozapine. Similar efficacy was observed in Kv3.2 knockout mice. In contrast, AUT1 was unable to prevent amphetamine-induced hyperactivity in mice lacking Kv3.1 channels. Notably, Kv3.1-null mice displayed baseline hyperlocomotion, reduced anxiety-like behavior, and antidepressant-like behavior. In ClockΔ19 mice, AUT1 reversed hyperactivity. Furthermore, AUT1 application modulated firing frequency and action potential properties of ClockΔ19 VTA dopamine neurons potentially through network effects. Kv3.1 protein levels in the VTA of ClockΔ19 and WT mice were unaltered by acute AUT1 treatment. Taken together, these results suggest that the modulation of Kv3.1 channels may provide a novel approach to the treatment of bipolar mania.
Assuntos
Acatisia Induzida por Medicamentos/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/tratamento farmacológico , Proteínas CLOCK , Neurônios Dopaminérgicos/efeitos dos fármacos , Hidantoínas/farmacologia , Piridinas/farmacologia , Canais de Potássio Shaw/metabolismo , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo , Anfetamina/farmacologia , Animais , Proteínas CLOCK/genética , Estimulantes do Sistema Nervoso Central/farmacologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Canais de Potássio Shaw/deficiênciaRESUMO
Experiments were conducted to develop a model to study the effect of oral and topical administration of the NK1 receptor antagonist aprepitant, on scratching behaviour in gerbils. The gerbil was selected due to its relevance for human NK1 receptor pharmacology. Intradermal injection of a specific NK1 receptor agonist GR73632 (100 nmol/100 µl) at the rostral back of gerbils produced scratching of the injection site. This could be attenuated by intradermal co-administration of a selective NK1 receptor antagonist aprepitant (30-100-300 nmol), demonstrating the role of dermal NK1 receptor in elicitation of scratching behaviour. Likewise, scratching was attenuated by oral (0.3-3-30 mg/kg) or topical application (0.01-0.1-1% w/v) of aprepitant and pharmacokinetic analysis of aprepitant levels in brain, blood and skin supported that efficacy of topically applied aprepitant was due to dermal rather than central target engagement. In conclusion, we showed that NK1 agonist-induced scratching in the gerbil can be reversed by systemic and topical administration of aprepitant. This test system may provide a useful model for the in vivo assessment of putative antipruritic agents.
Assuntos
Antipruriginosos/administração & dosagem , Morfolinas/administração & dosagem , Antagonistas dos Receptores de Neurocinina-1/administração & dosagem , Administração Oral , Administração Tópica , Animais , Aprepitanto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Gerbillinae , Humanos , Injeções Intradérmicas , Fragmentos de Peptídeos/administração & dosagem , Prurido/induzido quimicamente , Prurido/tratamento farmacológico , Receptores da Neurocinina-1/agonistas , Substância P/administração & dosagem , Substância P/análogos & derivadosRESUMO
A pharmacophore model for triple reuptake inhibitors and the new class of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes were recently reported. Further investigation in this area led to the identification of a new series of potent and selective triple reuptake inhibitors endowed with good developability characteristics. Excellent bioavailability and brain penetration are associated with this series of 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanes together with high in vitro potency and selectivity at SERT, NET, and DAT. In vivo microdialysis experiments in different animal models and receptor occupancy studies in rat confirmed that derivative 17 showed an appropriate profile to guarantee further progression of the compound.
Assuntos
Transtorno Depressivo/tratamento farmacológico , Heptanos/química , Heptanos/farmacologia , Inibidores da Captação de Neurotransmissores/química , Inibidores da Captação de Neurotransmissores/farmacologia , Animais , Antidepressivos/síntese química , Antidepressivos/química , Antidepressivos/farmacologia , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Encéfalo/metabolismo , Transtorno Depressivo/metabolismo , Dopamina/metabolismo , Heptanos/síntese química , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Camundongos , Microdiálise , Modelos Moleculares , Inibidores da Captação de Neurotransmissores/síntese química , Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Relação Estrutura-AtividadeRESUMO
The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SAR. Appropriate decoration of the scaffolds was achieved with the help of a triple reuptake inhibitor pharmacophore model detailed here. Selected derivatives showed good oral bioavailability (>30%) and brain penetration (B/B > 4) in rats associated with high in vitro potency and selectivity at SERT, NET, and DAT. Among these compounds, microdialysis and in vivo experiments confirm that derivative 15 has an appropriate developability profile to be considered for further progression.
Assuntos
Compostos Azabicíclicos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Animais , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacocinética , Ligação Competitiva , Monoaminas Biogênicas/metabolismo , Disponibilidade Biológica , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Masculino , Camundongos , Microdiálise , Microssomos Hepáticos/metabolismo , Modelos Químicos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
The 5-HT1B receptor has attracted significant interest as a potential target for the development of therapeutics for the treatment of affective disorders such as anxiety and depression. Here we present the in vivo characterisation of a novel, selective and orally bioavailable 5-HT1B receptor antagonist, SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride). SB-616234-A reversed the 5-HT1/7 receptor agonist, SKF-99101H-induced hypothermia in guinea pigs in a dose related manner with an ED50 of 2.4 mg/kg p.o. Using in vivo microdialysis in freely moving guinea pigs, SB-616234-A (3-30 mg/kg p.o.) caused a dose-related increase in extracellular 5-HT in the dentate gyrus. Evaluation of antidepressant- and anxiolytic-like effects of this 5-HT1B receptor antagonist was performed in a variety of models and species. SB-616234-A produced a decrease in immobility time in the mouse forced swim test; an effect suggestive of antidepressant activity. Furthermore, SB-616234-A produced dose-related anxiolytic effects in both rat and guinea pig maternal separation-induced vocalisation models with an ED50 of 1.0 and 3.3 mg/kg i.p., respectively (vs fluoxetine treatment ED50 = 2.2 mg/kg i.p. in both species). Also a significant reduction in posturing behaviours was observed in the human threat test in marmosets; an effect indicative of anxiolytic activity. In summary, SB-616234-A is a novel, potent and orally bioavailable 5-HT1B receptor antagonist which exhibits a neurochemical and behavioural profile that is consistent with both anxiolytic- and antidepressant-like activity in a variety of species. Taken together these data suggest that SB-616234-A may have therapeutic efficacy in the treatment of affective disorders.
Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Análise de Variância , Animais , Callithrix , Relação Dose-Resposta a Droga , Interações Medicamentosas , Cobaias , Hipotermia/induzido quimicamente , Hipotermia/tratamento farmacológico , Resposta de Imobilidade Tônica/efeitos dos fármacos , Indóis/farmacologia , Indóis/toxicidade , Masculino , Atividade Motora/efeitos dos fármacos , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Natação/psicologia , Fatores de Tempo , Vocalização Animal/efeitos dos fármacosRESUMO
We tested fluoxetine, bupropion and GR 205171, a selective neurokinin-1 receptor antagonist on forced swimming test (FST) response and on levels of monoamines in frontal cortex of CD1 mice by microdialysis techniques. All drugs decreased immobility time. Fluoxetine augmented all monoamines, bupropion enhanced catecholamines, and GR 205171 was totally ineffective. Results suggest that FST response may not be related to levels of monoamines in the mouse frontal cortex.