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1.
Alzheimers Dement (N Y) ; 8(1): e12274, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35415206

RESUMO

Introduction: The neuronal mechanism driving Alzheimer's disease (AD) is incompletely understood. Methods: Immunohistochemistry, pharmacology, biochemistry, and behavioral testing are employed in two pathological contexts-AD and a transgenic mouse model-to investigate T14, a 14mer peptide, as a key signaling molecule in the neuropathology. Results: T14 increases in AD brains as the disease progresses and is conspicuous in 5XFAD mice, where its immunoreactivity corresponds to that seen in AD: neurons immunoreactive for T14 in proximity to T14-immunoreactive plaques. NBP14 is a cyclized version of T14, which dose-dependently displaces binding of its linear counterpart to alpha-7 nicotinic receptors in AD brains. In 5XFAD mice, intranasal NBP14 for 14 weeks decreases brain amyloid and restores novel object recognition to that in wild-types. Discussion: These findings indicate that the T14 system, for which the signaling pathway is described here, contributes to the neuropathological process and that NBP14 warrants consideration for its therapeutic potential.

2.
Curr Opin Pharmacol ; 35: 94-100, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28803835

RESUMO

Receptor distribution studies have played a key role in the characterization of receptor systems (e.g. GABAB, NMDA (GluNRs), and Neurokinin 1) and in generating hypotheses to exploit these systems as potential therapeutic targets. Distribution studies can provide important information on the potential role of candidate receptors in normal physiology/disease and alert for possible adverse effects of targeting the receptors. Moreover, they can provide valuable information relating to quantitative target engagement (e.g. % receptor occupancy) to drive mechanistic pharmacokinetic/pharmacodynamic (PK/PD) hypotheses for compounds in the Drug Discovery process. Finally, receptor distribution and quantitative target engagement studies can be used to validate truly translational technologies such as PET ligands and pharmacoEEG paradigms to facilitate bridging of the preclinical/clinical interface and thus increase probability of success.


Assuntos
Receptores de GABA-B/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Receptores da Neurocinina-1/fisiologia , Animais , Humanos
3.
Exp Dermatol ; 24(4): 312-4, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25650546

RESUMO

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 & derivados
4.
Bioorg Med Chem ; 21(21): 6264-73, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24075145

RESUMO

The last two decades have provided a large weight of preclinical data implicating the neurokinin-1 receptor (NK1) and its cognate ligand substance P (SP) in a broad range of both central and peripheral disease conditions. However, to date, only the NK1 receptor antagonist aprepitant has been approved as a therapeutic and this is to prevent chemotherapy-induced nausea & vomiting (CINV). The belief remained that the full therapeutic potential of NK1 receptor antagonists had yet to be realized; therefore clinical evidence that NK1 receptor antagonists may be effective in major depression disorder, resulted in a significant further investment in discovering novel CNS penetrant druggable NK1 receptor antagonists to address this condition. At GlaxoSmithKline after the discovery of casopitant, that went on to demonstrate efficacy as a novel antidepressant in the clinic, additional novel analogues of this NK1 receptor antagonist were designed to further enhance its drug developability characteristics. Herein, we therefore describe the discovery process and the vivo pharmacological and pharmacokinetic profile of the new NK1 receptor antagonist 3a (also called orvepitant), selected as clinical candidate and further progressed into clinical studies for major depressive disorder. Moreover, molecular modeling studies enabled us to improve the pharmacophore model of the NK1 receptor antagonists with the identification of a region able to accommodate a variety of heterocycle moieties.


Assuntos
Antidepressivos/química , Antagonistas dos Receptores de Neurocinina-1/química , Receptores da Neurocinina-1/química , Animais , Antidepressivos/síntese química , Antidepressivos/farmacocinética , Comportamento Animal/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Células CHO , Cricetinae , Cricetulus , Cães , Feminino , Gerbillinae , Meia-Vida , Humanos , Masculino , Modelos Moleculares , Conformação Molecular , Antagonistas dos Receptores de Neurocinina-1/síntese química , Antagonistas dos Receptores de Neurocinina-1/farmacocinética , Piperazinas/química , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacocinética , Ligação Proteica , Ratos , Receptores da Neurocinina-1/genética , Receptores da Neurocinina-1/metabolismo
5.
Bioorg Med Chem Lett ; 21(18): 5562-7, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21831639

RESUMO

The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX(1) and the OX(2) receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX(1) receptor is highly expressed throughout the hypothalamus, whilst the OX(2) receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX(1) and OX(2) receptor antagonists, highly effective in a pre-clinical model of sleep.


Assuntos
Descoberta de Drogas , Piperidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Transtornos do Sono-Vigília/tratamento farmacológico , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Receptores de Orexina , Piperidinas/síntese química , Piperidinas/química , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
6.
J Med Chem ; 54(4): 1071-9, 2011 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-21229983

RESUMO

A large body of compelling preclinical evidence supports the clinical use of neurokinin (NK) receptor antagonists in a plethora of CNS and non-CNS therapeutic areas. The significant investment made in this area over the past 2 decades culminated with the observation that NK(1) receptor antagonists elicited clinical efficacy in major depression disorders. In addition, aprepitant (Merck) was launched as a new drug able to prevent chemotherapy-induced nausea and vomiting (CINV). After the discovery by GlaxoSmithKline of vestipitant, a wide drug discovery program was launched aimed at identifying additional clinical candidates. New compounds were designed to maximize affinity at the NK(1) receptor binding site while retaining suitable physicochemical characteristics to ensure excellent pharmacokinetic and pharmacodynamic properties in vivo. Herein we describe the discovery process of a new NK(1) receptor antagonist (casopitant) selected as clinical candidate and progressed into clinical studies to treat major depression disorders.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Transtorno Depressivo/tratamento farmacológico , Antagonistas dos Receptores de Neurocinina-1 , Piperazinas/síntese química , Piperazinas/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Células CHO , Cricetinae , Cricetulus , Transtorno Depressivo/metabolismo , Descoberta de Drogas , Gerbillinae , Meia-Vida , Humanos , Espectroscopia de Ressonância Magnética , Piperazinas/química , Piperazinas/farmacocinética , Piperidinas/química , Piperidinas/farmacocinética , Análise de Regressão , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho , Estereoisomerismo
7.
Pharmacol Biochem Behav ; 93(1): 17-24, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19358863

RESUMO

BACKGROUND: Converging findings support a role for extra-hypothalamic CRF in the mediation of the stress response. The influence of CRF in the amygdala is well established, while less is known of its role in other areas of the forebrain where CRF and CRF(1) receptors are also expressed. In the present study CRF was genetically induced to allow forebrain-restricted expression in a temporally-defined manner at any time during the mouse lifespan. This mouse model may offer the possibility to establish a model of the pathogenesis of recurrent episodes of depression. METHODS: Mice were engineered to carry both the rtTA transcription factor driven by the CamKII alpha promoter and the doxycycline-regulated operator (tetO) upstream of the CRF coding sequence. Molecular, biochemical and behavioural characterisation of this mouse is described. RESULTS: Following a three-week period of transcriptional induction, double transgenic mice showed approximately 2-fold increased expression of CRF mRNA in the hippocampus and cortex, but not hypothalamus. These changes were associated with 2-fold increase in morning corticosterone levels, although responses to the dexamethasone suppression test or acute stress were unaffected. In contrast, induced mice displayed modestly altered behaviour in the Light and Dark test and Forced Swim test. CONCLUSIONS: Transient induction of CRF expression in mouse forebrain was associated with endocrine and mild anxiety-like behavioural changes consistent with enhanced central CRF neurotransmission. This mouse allows the implementation of regimens with longer or repeated periods of induction which may model the initial stages of the pathology underlying recurrent depressive disorders.


Assuntos
Comportamento Animal/fisiologia , Corticosterona/sangue , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/fisiologia , Prosencéfalo/fisiologia , Animais , Ansiedade/etiologia , Ansiedade/genética , Ansiedade/fisiopatologia , Sequência de Bases , Comportamento Animal/efeitos dos fármacos , Primers do DNA/genética , Dexametasona/farmacologia , Modelos Animais de Doenças , Feminino , Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transtornos do Humor/etiologia , Transtornos do Humor/genética , Transtornos do Humor/fisiopatologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Estresse Fisiológico/genética , Estresse Fisiológico/fisiologia , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia
8.
J Med Chem ; 52(10): 3238-47, 2009 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-19388677

RESUMO

In an effort to discover novel druglike NK(1) receptor antagonists a new series of suitably substituted C-phenylpiperazine derivatives was identified by an appropriate chemical exploration of related N-phenylpiperazine analogues, with the specific aim to maximize their in vitro affinity and optimize in parallel their pharmacokinetic profile. Among the compounds synthesized, 2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant) was identified as one of the most in vitro potent and selective NK(1) receptor antagonists ever discovered, showing appropriate pharmacokinetic properties and in vivo activity. On the basis of its preclinical profile, this compound was selected as a drug candidate.


Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Piperazinas/química , Piperidinas/farmacologia , Administração Oral , Animais , Células CHO , Cricetinae , Cricetulus , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Fluorbenzenos , Gerbillinae , Farmacocinética , Piperazinas/farmacologia , Piperidinas/farmacocinética , Relação Estrutura-Atividade
9.
Addict Biol ; 12(1): 22-9, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17407494

RESUMO

Ghrelin is a brain-gut peptide with growth hormone-releasing and appetite-inducing activities. A growing body of evidence suggests that ghrelin may affect the central reward system and modulate the activity of the mesolimbic system. Recent clinical studies also showed a significant positive correlation between plasma ghrelin levels and craving in alcoholics. Accordingly, the present study investigated the potential role of serum ghrelin levels in the reinstatement of cocaine-seeking behaviour triggered by cocaine-associated cues. In addition, serum corticosterone levels were determined in the light of evidence suggesting that corticosterone plays a modulatory role in cocaine-seeking behaviour. Male Lister Hooded rats under a restricted diet regime were first trained to intravenously self-administer cocaine under a fixed ratio-1 schedule of reinforcement. Conditioned stimuli (CS: tone and cue-light on for 5 seconds) were presented contingently with cocaine delivery. Once a stable baseline of cocaine self-administration was observed, lever presses were extinguished to less than 30% of baseline rates by removing both cocaine and CS. Reinstatement of responding was then induced by re-exposure to cocaine-associated CS. Blood samples for the enzyme immunoassay determination of serum ghrelin and the radioimmunoassay determination of serum corticosterone levels were collected 30 minutes before the beginning of reinstatement sessions. Rats significantly reinstated their responding when exposed to CS. A positive and significant correlation was observed between ghrelin levels (r = 0.64; P < 0.05), but not corticosterone (r = 0.37; NS), and the increased active lever presses only in animals exposed to CS. These findings suggest a potential role of ghrelin in the modulation of cue-triggered reinstatement of cocaine-seeking behaviour.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Condicionamento Clássico/fisiologia , Motivação , Hormônios Peptídicos/sangue , Animais , Corticosterona/sangue , Sinais (Psicologia) , Grelina , Injeções Intravenosas , Masculino , Ratos , Esquema de Reforço , Autoadministração , Estatística como Assunto
10.
Peptides ; 27(12): 3202-7, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16959374

RESUMO

The involvement of Neuropeptide Y (NPY) in the pathophysiology of mood disorders has been suggested by clinical and preclinical evidence. NPY Y1 and Y2 receptors have been proposed to mediate the NPY modulation of stress responses and anxiety related behaviors. To further investigate the role of Y2 receptors in anxiety we studied the effect of BIIE0246, a selective Y2 receptor antagonist, in the elevated plus-maze test. Rats treated with 1.0 nmol BIIE0246 showed an increase in the time spent on the open arm of the maze. In addition, to study the effects of the Y2 antagonism on NPY protein level, NPY-like immunoreactivity was measured in different brain regions following treatment with BIIE0246, but no statistically significant effects were observed. These results suggest that BIIE0246 has an anxiolytic-like profile in the elevated plus-maze.


Assuntos
Ansiolíticos/farmacologia , Arginina/análogos & derivados , Benzazepinas/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Animais , Arginina/farmacologia , Masculino , Ratos
11.
Behav Brain Res ; 158(1): 123-32, 2005 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-15680200

RESUMO

Bipolar disorder is a psychiatric condition characterised by episodes of mania, depression, and underlying mood instability. Anticonvulsant drugs have an established place in the treatment of the disorder, but identifying novel drugs in this class is complicated by the absence of validated animal models. We have evaluated the efficacy of three anticonvulsant mood stabilising drugs (lamotrigine, valproate, and carbamazepine) in a model of mania, in which hyperactivity is induced by the combination of D-amphetamine and chlordiazepoxide. All three drugs were effective at preventing the hyperactivity. Lower doses of valproate and carbamazepine were required to prevent hyperactivity compared to doses required to block tonic-clonic seizures induced by pentylenetetrazole. Lamotrigine was equipotent in the two models. However, the complex pharmacology of the D-amphetamine/chlordiazepoxide model means that there may be several mechanisms by which hyperactivity can be reduced, and these may have more or less relevance to the treatment of bipolar disorder. To address this issue, we also evaluated effects of the three anticonvulsants on baseline locomotion, on activity in the presence of chlordiazepoxide alone, or on activity induced by D-amphetamine alone. Based on the results, we propose that hyperactivity induced by D-amphetamine/chlordiazepoxide may arise through dopaminergic drive coupled with disinhibition caused by low doses of the benzodiazepine. The efficacy of lamotrigine may then arise through a reduction in neuronal excitability or increased glutamate transmission, these latter a consequence of the disinhibition. Carbamazepine may also reduce excitability and glutamate release, but its broader pharmacology, manifested by sedation at higher doses complicates interpretation of its efficacy and reflects its poorer tolerability in the clinic. Valproate may be effective, at least in part, through an enhancement of GABAergic transmission. The predictive validity of the D-amphetamine/chlordiazepoxide model for efficacy in bipolar disorder remains to be established, and research with a wider range of clinically tested drugs is warranted to help validate the model further. In the meantime, the model may be useful for distinguishing novel anticonvulsant drugs with different mechanisms of action.


Assuntos
Anticonvulsivantes/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Carbamazepina/uso terapêutico , Triazinas/uso terapêutico , Ácido Valproico/uso terapêutico , Animais , Ansiolíticos/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Clordiazepóxido/farmacologia , Dextroanfetamina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Interações Medicamentosas , Quimioterapia Combinada , Lamotrigina , Camundongos , Atividade Motora/efeitos dos fármacos , Pentilenotetrazol/toxicidade , Agitação Psicomotora/tratamento farmacológico , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico
12.
Neurosci Lett ; 345(2): 73-6, 2003 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-12821174

RESUMO

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.


Assuntos
Antidepressivos/farmacologia , Monoaminas Biogênicas/metabolismo , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Natação , Tetrazóis/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Bupropiona/farmacologia , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Fluoxetina/farmacologia , Imobilização , Camundongos , Camundongos Endogâmicos , Córtex Pré-Frontal/metabolismo , Fatores de Tempo
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