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1.
Expert Opin Investig Drugs ; 30(3): 271-278, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33560891

RESUMO

BACKGROUND: MT-1207 is a novel multitarget blocker of α1 receptor, 5-HT2A receptor, and calcium channel that is currently under development for the treatment of hypertension. In this study, we evaluated the tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of MT-1207 in healthy Chinese subjects. RESEARCH DESIGN AND METHODS: We examined the effects of a single-ascending dose (SAD) of MT-1207 (5-40 mg) and MT-1207 (40 mg) administered in combination with food in 56 healthy subjects. RESULTS: No serious adverse events or discontinuations due to adverse events (related to MT-1207) occurred in either study. MT-1207 was rapidly absorbed (median Tmax: 0.5-1.25 h). The mean t1/2 of MT-1207 was approximately 4-7 hours. Systemic exposure (Cmax and AUC) to MT-1207 increased in proportion to dose. Food had little effect on the pharmacokinetics of MT-1207, such as t1/2 and AUC. For 4h-24 h after administration, the blood pressure reduction in the MT-1207 group was higher than that in the placebo group, showing the antihypertensive effect. Blood pressure reduction after MT-1207 administration showed some dose-dependent trend in the 5-20 mg groups. CONCLUSIONS: MT-1207 was well tolerated in all subjects. PD measurements demonstrated the antihypertensive effects of MT-1207.


Assuntos
Anti-Hipertensivos/administração & dosagem , Interações Alimento-Droga , Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos alfa 1/efeitos adversos , Antagonistas de Receptores Adrenérgicos alfa 1/farmacocinética , Adulto , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacocinética , Área Sob a Curva , Povo Asiático , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Antagonistas do Receptor 5-HT2 de Serotonina/efeitos adversos , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Adulto Jovem
2.
Neuropharmacology ; 168: 108009, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32145488

RESUMO

Cocaine use disorder (CUD) is a major public health challenge for which there are no pharmacotherapeutics approved by the United States Food and Drug Administration (FDA). The propensity to relapse in CUD involves several vulnerability factors including sensitivity to cues associated with cocaine-taking. Serotonin (5-hydroxytryptamine, 5-HT) neurotransmission, particularly through the 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR), is mechanistically linked to cocaine-seeking in preclinical models. In the present experiments, we employed self-administration assays in male rats to investigate whether acute and/or repeated administration of the FDA-approved selective 5-HT2AR antagonist/inverse agonist pimavanserin, selective 5-HT2CR agonist lorcaserin or their combination would alter cocaine intake and/or cocaine-seeking behavior. We found that acute administration of lorcaserin, but not pimavanserin, attenuated cocaine intake while pimavanserin plus lorcaserin did not impact cocaine self-administration. In contrast, 10-days of repeated administration of pimavanserin, lorcaserin, or pimavanserin plus lorcaserin during forced abstinence from cocaine self-administration, blunted cocaine-seeking, similar to the acute administration of each ligand. Taken together, these data reveal the efficacy of repeated treatment with pimavanserin plus lorcaserin to attenuate factors important to relapse-like behaviors in rodent models of CUD. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.


Assuntos
Benzazepinas/administração & dosagem , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Transtornos Relacionados ao Uso de Cocaína/psicologia , Cocaína/administração & dosagem , Piperidinas/administração & dosagem , Ureia/análogos & derivados , Animais , Benzazepinas/farmacocinética , Cocaína/farmacocinética , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Masculino , Piperidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Recidiva , Autoadministração , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Ureia/administração & dosagem , Ureia/farmacocinética
3.
Neuropharmacology ; 139: 61-67, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29969592

RESUMO

Blockade of serotonin 2A (5-HT2A) receptors is regarded as an anti-dyskinetic and anti-psychotic strategy in Parkinson's disease (PD). However, the 5-HT2A antagonists tested so far exhibited affinity for other receptors, which might have played a role in their action. EMD-281,014 is the most selective 5-HT2A antagonist available, with approximately 2,000-fold selectivity over serotonin 2C (5-HT2C) receptors. EMD-281,014 was previously tested in the clinic and has high translational potential. In the present study, we assessed the effect of EMD-281,014 on dyskinesia and psychosis in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset. We first determined the pharmacokinetic profile of EMD-281,014 in the marmoset, after which doses leading to clinically-relevant plasma levels (0.01, 0.03 and 0.1 mg/kg) or vehicle were administered to MPTP-lesioned marmosets, in combination with L-3,4-dihydroxyphenylalanine (l-DOPA). The effects of EMD-281,014 on dyskinesia, psychosis-like behaviours (PLBs) and parkinsonism were then evaluated. When added to l-DOPA, EMD-281,014 (0.03 and 0.1 mg/kg) reduced peak dose dyskinesia, by 41.8% and 54.5% (P < 0.05 and P < 0.001), when compared to l-DOPA/vehicle. EMD-281,014 (0.03 and 0.1 mg/kg) also significantly reduced the severity of peak dose PLBs, by 42.5% and 45.9% (P < 0.05 and P < 0.001), when compared to vehicle. The anti-dyskinetic and anti-psychotic effects of EMD-281,014 were achieved without interfering with l-DOPA anti-parkinsonian action. Our results suggest that highly-selective 5-HT2A receptor blockade with EMD-281,014 is an effective way to alleviate both dyskinesia and psychosis in PD, without adversely affecting parkinsonian disability.


Assuntos
Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/tratamento farmacológico , Indóis/farmacologia , Levodopa/efeitos adversos , Intoxicação por MPTP/tratamento farmacológico , Piperazinas/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Callithrix , Relação Dose-Resposta a Droga , Interações Medicamentosas , Discinesia Induzida por Medicamentos/metabolismo , Feminino , Indóis/farmacocinética , Intoxicação por MPTP/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Piperazinas/farmacocinética , Psicoses Induzidas por Substâncias/tratamento farmacológico , Psicoses Induzidas por Substâncias/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética
4.
J Pharmacol Exp Ther ; 365(3): 624-635, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29615471

RESUMO

Multitarget antidepressants selectively inhibiting monoaminergic transporters and 5-hydroxytryptamine (5-HT) 2A receptor have demonstrated higher efficacy and fewer side effects than selective serotonin reuptake inhibitors. In the present study, we synthesized a series of novel 3-(benzo[d][1,3]dioxol-4-yloxy)-3-arylpropyl amine derivatives, among which compound H05 was identified as a lead, exhibiting potent inhibitory effects on both serotonin (Ki = 4.81 nM) and norepinephrine (NE) (Ki = 6.72 nM) transporters and moderate 5-HT2A antagonist activity (IC50 = 60.37 nM). H05 was able to dose-dependently reduce the immobility duration in mouse forced swimming test and tail suspension test, with the minimal effective doses lower than those of duloxetine, and showed no stimulatory effect on locomotor activity. The administration of H05 (5, 10, and 20 mg/kg, by mouth) significantly shortened the immobility time of adrenocorticotropin-treated rats that serve as a model of treatment-resistant depression, whereas imipramine (30 mg/kg, by mouth) and duloxetine (30 mg/kg, by mouth) showed no obvious effects. Chronic treatment with H05 reversed the depressive-like behaviors in a rat model of chronic unpredictable mild stress and a mouse model of corticosterone-induced depression. Microdialysis analysis revealed that the administration of H05 at either 10 or 20 mg/kg increased the release of 5-HT and NE from the frontal cortex. The pharmacokinetic (PK) and brain penetration analyses suggest that H05 has favorable PK properties with good blood-brain penetration ability. Therefore, it can be concluded that H05, a novel serotonin and NE reuptake inhibitor with 5-HT2A antagonist activity, possesses efficacious activity in the preclinical models of depression and treatment-resistant depression, and it may warrant further evaluation for clinical development.


Assuntos
Aminas/farmacologia , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Receptor 5-HT2A de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Aminas/metabolismo , Aminas/farmacocinética , Aminas/uso terapêutico , Animais , Antidepressivos/metabolismo , Antidepressivos/farmacocinética , Antidepressivos/uso terapêutico , Barreira Hematoencefálica/metabolismo , Masculino , Camundongos , Ratos , Antagonistas do Receptor 5-HT2 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Antagonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Inibidores da Recaptação de Serotonina e Norepinefrina/metabolismo , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacocinética , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico
5.
J Clin Pharm Ther ; 42(5): 598-606, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28608926

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Flibanserin is a serotonin 5-HT1A agonist and 5-HT2A antagonist approved for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Because of the increased risk of hypotension- and syncope-related adverse events (AEs) observed with coadministration of flibanserin and alcohol, alcohol use is contraindicated. To provide a more comprehensive understanding of the interaction between flibanserin and alcohol, the results of a dedicated phase 1 alcohol-interaction study and a pooled analysis of phase 3 studies of premenopausal women with HSDD are presented. METHODS: In the phase 1 study, healthy participants (males [n=23] and females [n=2]) were randomly assigned to one of five sequence groups, which determined the order in which they were to receive flibanserin 100 mg or placebo, with or without ethanol 0.4 g/kg or 0.8 g/kg. Change from baseline in seated blood pressure, orthostatic vital signs, AEs and visual analogue scale sedation outcomes were examined. Blood samples were collected at baseline and for up to 4 hours after dosing to determine flibanserin area under the plasma concentration-time curve from 0 to 4 hours (AUC0-4 ). Pooled data from five phase 3 studies of patients receiving flibanserin 100 mg once daily (n=1543), or placebo (n=1905), were analysed. RESULTS: In the phase 1 study, the incidence of hypotension and syncope increased when flibanserin was coadministered with ethanol. Sedation increased 20% and 27% from baseline with flibanserin plus ethanol 0.4 g/kg and 0.8 g/kg, respectively, at 4 hours post-dose. In the pooled analysis of phase 3 studies, 58.2% and 63.6% of participants receiving flibanserin or placebo, respectively, reported baseline alcohol use. In patients receiving flibanserin, fatigue and dizziness occurred more frequently in patients with vs. without alcohol use. WHAT IS NEW AND CONCLUSION: Results from this study suggest that increased incidence of hypotension- and syncope-related events may result from a pharmacodynamic interaction between flibanserin and alcohol, although the clinical significance of these interactions in real-world populations remains unclear.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Benzimidazóis/administração & dosagem , Pré-Menopausa , Disfunções Sexuais Psicogênicas/tratamento farmacológico , Adulto , Área Sob a Curva , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Método Duplo-Cego , Interações Medicamentosas , Fadiga/induzido quimicamente , Fadiga/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Agonistas do Receptor 5-HT1 de Serotonina/efeitos adversos , Agonistas do Receptor 5-HT1 de Serotonina/farmacocinética , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Antagonistas do Receptor 5-HT2 de Serotonina/efeitos adversos , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Síncope/induzido quimicamente , Síncope/epidemiologia , Adulto Jovem
6.
Expert Opin Drug Metab Toxicol ; 13(8): 891-896, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28636828

RESUMO

INTRODUCTION: Lorcaserin is a serotonin 2C receptor antagonist that was FDA approved in 2012. Lorcaserin is recently available as an extended-release (ER) formulation for the treatment of obesity as an adjunct to lifestyle modification. Areas covered: The pharmacokinetics, pharmacodynamics, efficacy, and safety of lorcaserin ER will be reviewed. Expert opinion: Lorcaserin ER 20mg daily provides drug exposure bioequivalent to lorcaserin immediate release (IR) 10mg twice daily. Lorcaserin IR is associated with 3.3 and 3.0% placebo-subtracted weight loss in patients without and with diabetes, respectively. A1C was reduced by 0.9% in patients with diabetes. Common side effects include headache, dry mouth, constipation, dizziness, fatigue, and nausea. Lorcaserin provides potential advantages over other antiobesity medications in regards to tolerability and simplicity of medication initiation, but may not be as effective as other options. Lorcaserin ER offers improved ease of administration and anticipated adherence compared to the IR formulation. The place in therapy for lorcaserin ER and other antiobesity medications will be further clarified by results of pending clinical trials addressing cardiovascular outcomes as well as the role pharmacogenomics and comorbid disease states may play in choosing patient-specific therapy.


Assuntos
Fármacos Antiobesidade/administração & dosagem , Benzazepinas/administração & dosagem , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/farmacocinética , Benzazepinas/efeitos adversos , Benzazepinas/farmacocinética , Preparações de Ação Retardada , Humanos , Adesão à Medicação , Obesidade/tratamento farmacológico , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Antagonistas do Receptor 5-HT2 de Serotonina/efeitos adversos , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Redução de Peso/efeitos dos fármacos
7.
Clin Pharmacokinet ; 56(5): 493-503, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27722855

RESUMO

Lurasidone hydrochloride, a benzisothiazol derivative, is a second-generation (atypical) antipsychotic agent that has received regulatory approval for the treatment of schizophrenia in the US, Canada, the EU, Switzerland, and Australia, and also for bipolar depression in the US and Canada. In addition to its principal antagonist activity at dopamine D2 and serotonin 5-HT2A receptors, lurasidone has distinctive 5-HT7 antagonistic activity, and displays partial agonism at 5-HT1A receptors, as well as modest antagonism at noradrenergic α2A and α2C receptors. Lurasidone is devoid of antihistaminic and anticholinergic activities. It is administered once daily within the range of 40-160 mg/day for schizophrenia and 20-120 mg/day for bipolar depression, and its pharmacokinetic profile requires administration with food. In adult healthy subjects and patients, a 40 mg dose results in peak plasma concentrations in 1-3 h, a mean elimination half-life of 18 h (mostly eliminated in the feces), and apparent volume of distribution of 6173 L; it is approximately 99 % bound to serum plasma proteins. Lurasidone's pharmacokinetics are approximately dose proportional in healthy adults and clinical populations within the approved dosing range, and this was also found in a clinical study of children and adolescents. Lurasidone is principally metabolized by cytochrome P450 (CYP) 3A4 with minor metabolites and should not be coadministered with strong CYP3A4 inducers or inhibitors. Lurasidone does not significantly inhibit or induce CYP450 hepatic enzymes.


Assuntos
Antipsicóticos/farmacocinética , Cloridrato de Lurasidona/farmacocinética , Esquizofrenia/sangue , Esquizofrenia/tratamento farmacológico , Fatores Etários , Animais , Antipsicóticos/uso terapêutico , Citocromo P-450 CYP3A/metabolismo , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Cloridrato de Lurasidona/uso terapêutico , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Antagonistas do Receptor 5-HT2 de Serotonina/uso terapêutico
8.
Acta Pharm ; 66(4): 555-562, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27749254

RESUMO

The aim of this study was to prepare a nasal gel of risperidone and to investigate the pharmacokinetics and relative bioavailability of the drug in rats. Compared with oral dosing, the risperidone nasal gel exhibited very fast absorption and high bioavailability. Maximal plasma concentration (cmax) and the time to reach cmax (tmax) were 15.2 µg mL-1 and 5 min for the nasal gel, 3.6 µg mL-1 and 30 min for the oral drug suspension, respectively. Pharmacokinetic parameters such as tmax', cmax and AUC of oral and nasal routes were significantly different (p < 0.01). Relative bioavailability of the drug nasal preparation to the oral suspension was up to 1600.0 %. Further, the in vitro effect of the risperidone nasal gel on nasal mucociliary movement was also investigated using a toad palate model. The risperidone nasal formulation showed mild ciliotoxicity, but the adverse effect was temporary and reversible.


Assuntos
Antipsicóticos/administração & dosagem , Antagonistas dos Receptores de Dopamina D2/administração & dosagem , Sistemas de Liberação de Medicamentos , Absorção Nasal , Mucosa Nasal/metabolismo , Risperidona/administração & dosagem , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Administração Intranasal , Animais , Antipsicóticos/efeitos adversos , Antipsicóticos/sangue , Antipsicóticos/farmacocinética , Anuros , Disponibilidade Biológica , Cílios/efeitos dos fármacos , Cílios/metabolismo , Antagonistas dos Receptores de Dopamina D2/efeitos adversos , Antagonistas dos Receptores de Dopamina D2/sangue , Antagonistas dos Receptores de Dopamina D2/farmacocinética , Composição de Medicamentos , Géis , Técnicas In Vitro , Masculino , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/metabolismo , Mucosa Nasal/efeitos dos fármacos , Palato , Distribuição Aleatória , Ratos Wistar , Risperidona/efeitos adversos , Risperidona/sangue , Risperidona/farmacocinética , Antagonistas do Receptor 5-HT2 de Serotonina/efeitos adversos , Antagonistas do Receptor 5-HT2 de Serotonina/sangue , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética
9.
Neuroimage ; 130: 167-174, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26876490

RESUMO

INTRODUCTION: [(11)C]Cimbi-36 is a recently developed serotonin 2A (5-HT2A) receptor agonist positron emission tomography (PET) radioligand that has been successfully applied for human neuroimaging. Here, we investigate the test-retest variability of cerebral [(11)C]Cimbi-36 PET and compare [(11)C]Cimbi-36 and the 5-HT2A receptor antagonist [(18)F]altanserin. METHODS: Sixteen healthy volunteers (mean age 23.9 ± 6.4years, 6 males) were scanned twice with a high resolution research tomography PET scanner. All subjects were scanned after a bolus of [(11)C]Cimbi-36; eight were scanned twice to determine test-retest variability in [(11)C]Cimbi-36 binding measures, and another eight were scanned after a bolus plus constant infusion with [(18)F]altanserin. Regional differences in the brain distribution of [(11)C]Cimbi-36 and [(18)F]altanserin were assessed with a correlation of regional binding measures and with voxel-based analysis. RESULTS: Test-retest variability of [(11)C]Cimbi-36 non-displaceable binding potential (BPND) was consistently <5% in high-binding regions and lower for reference tissue models as compared to a 2-tissue compartment model. We found a highly significant correlation between regional BPNDs measured with [(11)C]Cimbi-36 and [(18)F]altanserin (mean Pearson's r: 0.95 ± 0.04) suggesting similar cortical binding of the radioligands. Relatively higher binding with [(11)C]Cimbi-36 as compared to [(18)F]altanserin was found in the choroid plexus and hippocampus in the human brain. CONCLUSIONS: Excellent test-retest reproducibility highlights the potential of [(11)C]Cimbi-36 for PET imaging of 5-HT2A receptor agonist binding in vivo. Our data suggest that Cimbi-36 and altanserin both bind to 5-HT2A receptors, but in regions with high 5-HT2C receptor density, choroid plexus and hippocampus, the [(11)C]Cimbi-36 binding likely represents binding to both 5-HT2A and 5-HT2C receptors.


Assuntos
Benzilaminas/farmacocinética , Encéfalo/metabolismo , Ketanserina/análogos & derivados , Fenetilaminas/farmacocinética , Agonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Benzilaminas/metabolismo , Radioisótopos de Carbono/metabolismo , Radioisótopos de Carbono/farmacocinética , Feminino , Radioisótopos de Flúor/metabolismo , Radioisótopos de Flúor/farmacocinética , Humanos , Ketanserina/metabolismo , Ketanserina/farmacocinética , Masculino , Neuroimagem/métodos , Fenetilaminas/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Reprodutibilidade dos Testes , Agonistas do Receptor 5-HT2 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/metabolismo , Adulto Jovem
10.
ACS Chem Neurosci ; 5(7): 611-5, 2014 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-24845956

RESUMO

Several voids exist in reliable positron emission tomography (PET) radioligands for quantification of the serotonin (5HT) receptor system. Even in cases where 5HT radiotracers exist, challenges remain that have limited the utility of 5HT imaging in clinical research. Herein we address an unmet need in 5HT2a imaging using innovative chemistry. We report a scalable and robust synthesis of [(18)F]MDL100907, which was enabled by a Ni-mediated oxidative fluorination using [(18)F]fluoride. This first demonstration of a Ni-mediated fluorination used for PET imaging required development of a new reaction strategy that ultimately provided high specific activity [(18)F]MDL100907. Using the new synthetic strategy and optimized procedure, [(18)F]MDL100907 was evaluated against [(11)C]MDL100907 for reliability to quantify 5HT2a in the nonhuman primate brain and was found to be superior based on a single scan analysis using the same nonhuman primate. The use of this new 5HT2a radiotracer will afford clinical neuroscience research the ability to distinguish 5HT2a receptor abnormalities binding between healthy subjects and patients even when group differences are small.


Assuntos
Encéfalo/diagnóstico por imagem , Radioisótopos de Flúor , Fluorbenzenos , Piperidinas , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Antagonistas do Receptor 5-HT2 de Serotonina , Animais , Encéfalo/metabolismo , Radioisótopos de Carbono/química , Radioisótopos de Carbono/farmacocinética , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacocinética , Fluorbenzenos/síntese química , Fluorbenzenos/farmacocinética , Halogenação , Imageamento por Ressonância Magnética , Papio anubis , Piperidinas/síntese química , Piperidinas/farmacocinética , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Receptor 5-HT2A de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/síntese química , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Fatores de Tempo
11.
Bioorg Med Chem Lett ; 24(9): 2118-22, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24717153

RESUMO

This Letter describes our attempts to elaborate dually acting compounds possessing serotonin re-uptake transporter inhibitor and serotonin 5-HT2C receptor antagonist properties. A novel series of 1,3-diphenylureas and N-phenylbenzamides have thus been prepared and evaluated. Based on its in vitro and in vivo activities, as well as pharmacokinetic profile, compound 16a was identified as a lead compound. The synthesis and structure-activity relationship of this series of compounds is presented herein.


Assuntos
Benzamidas/química , Benzamidas/farmacologia , Carbanilidas/química , Carbanilidas/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/química , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Benzamidas/farmacocinética , Carbanilidas/farmacocinética , Desenho de Fármacos , Humanos , Ligantes , Camundongos , Modelos Moleculares , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Relação Estrutura-Atividade
12.
J Psychopharmacol ; 27(4): 396-400, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23427194

RESUMO

Second-generation antipsychotics, which have become the standard drug therapies for schizophrenia, are known to have a serotonin 5-HT(2A) receptor blocking effect in addition to a dopamine D2 receptor blocking effect. However, although chlorpromazine (CPZ) has a 5-HT(2A) receptor blocking effect and has the profile of a second-generation antipsychotic in vitro, it loses this pharmacological profile in vivo. In order to elucidate the differences between the in vivo and in vitro pharmacological characteristics of CPZ, we used a radioreceptor assay to measure the anti-D2 activity and the anti-5-HT(2A) activity of CPZ and five major metabolites of CPZ, and compared the results to the anti-D2 activity and anti-5-HT(2A) activity of risperidone, zotepine, perospirone, the major metabolites of each of these drugs, and olanzapine, bromperidol, and haloperidol. The subjects were 182 patients who had received diagnoses of schizophrenia based on the DSM-IV criteria. The results revealed that CPZ exhibited little anti-5-HT(2A) activity, regardless of the anti-D2 activity level, and that none of the metabolites possessed anti-5-HT(2A) activity. However, both the parent compounds and the metabolites of each of the second-generation antipsychotics possessed both anti-D2 activity and anti-5-HT(2A) activity. This clarified that, unlike second-generation antipsychotics, the reason CPZ loses its second-generation antipsychotic profiles in vivo is because it does not have any metabolites that possess anti-5-HT(2A) activity.


Assuntos
Antipsicóticos/farmacocinética , Encéfalo/efeitos dos fármacos , Antagonistas de Dopamina/farmacocinética , Antagonistas dos Receptores de Dopamina D2 , Neurônios/efeitos dos fármacos , Esquizofrenia/sangue , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Adulto , Algoritmos , Antipsicóticos/sangue , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Biotransformação , Encéfalo/metabolismo , Clorpromazina/sangue , Clorpromazina/farmacocinética , Clorpromazina/farmacologia , Clorpromazina/uso terapêutico , Manual Diagnóstico e Estatístico de Transtornos Mentais , Antagonistas de Dopamina/sangue , Antagonistas de Dopamina/farmacologia , Antagonistas de Dopamina/uso terapêutico , Feminino , Haloperidol/análogos & derivados , Haloperidol/sangue , Haloperidol/farmacocinética , Haloperidol/farmacologia , Haloperidol/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/sangue , Antagonistas do Receptor 5-HT2 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Adulto Jovem
13.
Eur J Pharmacol ; 682(1-3): 142-52, 2012 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-22374259

RESUMO

Central and peripheral 5-hydroxytryptamine (5-HT) receptors play a critical role in the regulation of micturition. Bolus doses of 5-HT(2A/2C) receptor agonists have been shown to activate the external urethral sphincter (EUS) and to inhibit micturition. This study was designed to determine the contribution of these two 5-HT receptor subtypes to activation of the EUS and inhibition of micturition utilising pharmacokinetic knowledge to better control drug exposure. Recordings of urethral and bladder pressure, EUS-Electromyogram (EMG), the micturition reflex induced by bladder filling, blood pressure and heart rate were made in anaesthetized female rats. The effects of intravenous (i.v.) infusions of the 5-HT(2) receptor agonist (2S)-1-(6-chloro-5-fluoroindol-1-yl)propan-2-amine fumarate (Ro 60-0175) in the absence or presence of the selective 5-HT(2C) receptor antagonist 6-chloro-5-methyl-N-[6-(2-methylpyridin-3-yl)oxypyridin-3-yl]-2,3-dihydroindole-1-carboxamide dihydrochloride (SB 242084) or 5-HT(2A) receptor antagonist (R)-(2,3-dimethoxyphenyl)-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol (MDL-100,907) were studied on these variables. Continuous infusion of increasing concentrations of Ro 60-0175 only evoked EUS-EMG activity at the highest concentration, which was blocked by co-infusion of MDL-100,907 but not SB 242084. Urethral pressure was unaffected by any drug infusion. Ro 60-0175 at the lowest concentration inhibited the micturition reflex but as the concentration increased this was reversed to facilitation. SB 242084 blocked the inhibition while MDL-100,907 blocked the excitation. Activation of 5-HT(2A) not 5-HT(2C) receptors evoked EUS-EMG activity. In conclusion, 5-HT(2A) receptor activation facilitated the micturition reflex and evoked EUS-EMG while 5-HT(2C) receptor activation only inhibited the micturition reflex.


Assuntos
Músculo Esquelético/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Uretra/metabolismo , Micção/efeitos dos fármacos , Anestesia , Animais , Pressão Sanguínea/efeitos dos fármacos , Interações Medicamentosas , Eletromiografia , Feminino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Ratos , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Uretra/efeitos dos fármacos , Uretra/fisiologia
15.
Neuropsychopharmacology ; 37(6): 1465-73, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22353758

RESUMO

3,4-Methylenedioxymethamphetamine (MDMA), the main psychoactive component of the recreational drug ecstasy, is a potent serotonin (5-HT) releaser. In animals, MDMA induces 5-HT depletion and toxicity in 5-HT neurons. The aim of this study was to investigate both presynaptic (5-HT transporter, SERT) and postsynaptic (5-HT(2A) receptor) markers of 5-HT transmission in recently abstinent chronic MDMA users compared with matched healthy controls. We hypothesized that MDMA use is associated with lower SERT density and concomitant upregulation of 5-HT(2A) receptors. Positron emission tomography studies using the SERT ligand [¹¹C]DASB and the 5-HT(2A) receptor ligand [¹¹C]MDL 100907 were evaluated in 13 current and recently detoxified MDMA users and 13 matched healthy controls. MDMA users reported a mean duration of ecstasy use of 8 years, regular exposure, and at least 2 weeks of abstinence before the scans. SERT and 5-HT(2A) receptor availability (binding potential, BP(ND)) were analyzed with a two-tissue compartment model with arterial input function. Current recreational MDMA use was significantly associated with lower SERT BP(ND) and higher 5-HT(2A) receptor BP(ND) in cortical, but not subcortical regions. Decreased SERT BP(ND) was regionally associated with upregulated 5-HT(2A) receptor BP(ND). In light of the animal literature, the most parsimonious interpretation is that repeated exposure to MDMA in humans, even in moderate amounts, leads to damage in 5-HT neuron terminals innervating the cortex. Alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain MDMA use. The reversibility of these changes upon abstinence remains to be firmly established.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/patologia , Benzilaminas/farmacocinética , Fluorbenzenos/farmacocinética , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Neocórtex/diagnóstico por imagem , Piperidinas/farmacocinética , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico por imagem , Mapeamento Encefálico , Radioisótopos de Carbono/farmacocinética , Feminino , Humanos , Masculino , Neocórtex/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Ligação Proteica/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Adulto Jovem
16.
Eur J Clin Pharmacol ; 68(1): 29-37, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21739267

RESUMO

PURPOSE: To investigate the effects of coadministration of paroxetine or fluvoxamine on the pharmacokinetics of aripiprazole in healthy adult Japanese with different CYP2D6 genotypes. METHODS: Fourteen CYP2D6 extensive metabolizer (EM) and 14 CYP2D6 intermediate metabolizer (IM) subjects were coadministered a single oral dose of aripiprazole 3 mg after steady-state plasma concentrations of the SSRIs paroxetine (20 mg/day) or fluvoxamine (100 mg/day) were reached by repeated oral doses for 6-7 days. The pharmacokinetics of aripiprazole with and without coadministration of SSRIs were compared according to CYP2D6 genotypes. RESULTS: Coadministration of paroxetine, a potent CYP2D6 inhibitor, decreased systemic clearance (CL/F) of aripiprazole by 58 and 23% in CYP2D6 EMs and IMs, respectively, demonstrating that the percentage inhibition of CYP2D6 activity by coadministration of paroxetine was apparently greater in CYP2D6 EMs than in IMs. Coadministration of fluvoxamine, a less potent CYP3A4 inhibitor, decreased the CL/F of aripiprazole by 39% in CYP2D6 EMs and 40% in IMs, indicating the same inhibitory effect on CYP enzymes, regardless of the CYP2D6 genotype. Percent contribution of CYP2D6 to total CL/F (CYP2D6 plus CYP3A4) of aripiprazole estimated as a reduced percentage of CL/F by CYP enzyme inhibition was 62% for CYP2D6 EMs and 24% for IMs in paroxetine coadministration, and 40% for CYP2D6 EMs and 18% for IMs in fluvoxamine coadministration. CONCLUSIONS: There were marked differences in the degree of influence of paroxetine coadministration on the pharmacokinetics of aripiprazole between CYP2D6 EMs and IMs, but no apparent differences were found between two CYP2D6 genotypes in fluvoxamine coadministration. Aripiprazole can be used safely in combination with SSRIs that have a CYP enzyme-inhibitory action.


Assuntos
Antipsicóticos/farmacocinética , Citocromo P-450 CYP2D6/genética , Fluvoxamina/farmacologia , Paroxetina/farmacologia , Piperazinas/farmacocinética , Polimorfismo Genético , Quinolonas/farmacocinética , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Adulto , Antipsicóticos/efeitos adversos , Antipsicóticos/sangue , Aripiprazol , Biotransformação , Citocromo P-450 CYP2D6/metabolismo , Inibidores do Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Interações Medicamentosas , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/farmacologia , Fluvoxamina/efeitos adversos , Fluvoxamina/sangue , Estudos de Associação Genética , Meia-Vida , Humanos , Japão , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Paroxetina/efeitos adversos , Paroxetina/sangue , Piperazinas/efeitos adversos , Piperazinas/sangue , Quinolonas/efeitos adversos , Quinolonas/sangue , Antagonistas do Receptor 5-HT2 de Serotonina/efeitos adversos , Antagonistas do Receptor 5-HT2 de Serotonina/sangue , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/sangue , Adulto Jovem
17.
Eur J Pharmacol ; 670(1): 195-203, 2011 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-21914448

RESUMO

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by sustained elevation of pulmonary arterial pressure that leads to right ventricle failure and death. Pulmonary resistance arterioles in PAH undergo progressive narrowing and/or occlusion. Currently approved therapies for PAH are directed primarily at relief of symptoms by interfering with vasoconstrictive signals, but do not halt the microvascular cytoproliferative process. In this study we show that C-122 (2-amino-N-(2-{4-[3-(2-trifluoromethyl-phenothiazin-10-yl)-propyl]-piperazin-1-yl}-ethyl)-acetamide trihydrochloride, a novel antagonist of serotonin receptor 5-HT(2B) (Ki=5.2 nM, IC(50)=6.9 nM), when administered to rats for three weeks in daily oral 10mg/kg doses, prevents not only monocrotaline (MCT)-induced elevations in pressure in the pulmonary arterial circuit (19 ± 0.9 mmHg vs. 28 ± 2 mmHg in MCT-vehicle group, P<0.05) and hypertrophy of the right ventricle (right ventricular wt./body wt. ratio 0.52 ± 0.02 vs. 0.64 ± 0.04 in MCT-vehicle group, P<0.05), but also muscularization of pulmonary arterioles (23% vs. 56% fully muscularized in MCT-vehicle group, P<0.05), and perivascular fibrosis in the lung. C-122 is orally absorbed in the rat, and partitions strongly into multiple tissues, including heart and lung. C-122 has significant off-target antagonist activity for histamine H-1 and several dopamine receptors, but shows no evidence of crossing the blood-brain barrier after a single 10mg/kg oral dose in rats. We conclude that C-122 can prevent microvascular remodeling and associated elevated pressures in the rat MCT model for PAH, and offers promise as a new therapeutic entity to suppress vascular smooth muscle cell proliferation in PAH patients.


Assuntos
Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/prevenção & controle , Monocrotalina/efeitos adversos , Fenotiazinas/farmacologia , Piperazinas/farmacologia , Receptor 5-HT2B de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/fisiopatologia , Transporte Biológico , Proteínas Sanguíneas/metabolismo , Hipertensão Pulmonar Primária Familiar , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Hipertrofia/prevenção & controle , Masculino , Fenotiazinas/administração & dosagem , Fenotiazinas/metabolismo , Fenotiazinas/farmacocinética , Piperazinas/administração & dosagem , Piperazinas/metabolismo , Piperazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Antagonistas do Receptor 5-HT2 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética
18.
J Med Chem ; 54(18): 6305-18, 2011 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-21823597

RESUMO

Serotonin antagonist reuptake inhibitor (SARI) drugs that block both 5-HT(2) receptors and the serotonin transporters have been developed. The human 5-HT(2A/2C) receptor has been implicated in several neurological conditions, and potent selective 5-HT(2A/2C) ligands may have therapeutic potential for treatment of CNS diseases such as depression. An imidazole moiety usually provides good pharmacokinetic properties as a drug substance, and thus considerable efforts have been devoted to develop imidazole derivatives into drug candidates. The imidazole series of compounds was evaluated against 5-HT(2A/2C) and serotonin reuptake inhibition. A few of the compounds in the series showed promising IC(50) values and antidepressant-like effect in in vivo forced swimming test (FST). On the basis of these results, further lead optimization studies resulted in identifying promising compounds potentially for therapeutic use.


Assuntos
Antidepressivos/síntese química , Imidazóis/síntese química , Piperazinas/síntese química , Receptor 5-HT2A de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Antagonistas do Receptor 5-HT2 de Serotonina/síntese química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Animais , Antidepressivos/farmacocinética , Antidepressivos/farmacologia , Ligação Competitiva , Células CHO , Cricetinae , Cricetulus , Desenho de Fármacos , Humanos , Imidazóis/farmacocinética , Imidazóis/farmacologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
19.
Biomed Chromatogr ; 24(11): 1159-67, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20954206

RESUMO

A simple LC-MS/MS method was developed and validated for the estimation of sarpogrelate in 50 µL of rat plasma. The analyte and internal standard (IS) were extracted from rat plasma by acetonitrile precipitation and they were separated on a reversed-phase C8 column with gradient program. The MS acquisition was performed with multiple reaction monitoring mode using m/z 430.2 to m/z 135.0 for analyte and m/z 448.2 to m/z 285.3 for IS. The calibration curves were linear over the range of 1-1000 ng/mL with the correlation coefficient greater than 0.999. With dilution integrity up to 20-fold, the upper limit of quantification was extendable up to 15,000 ng/mL. The method was successfully applied to the analysis of rat plasma samples after single dose oral administration of sarpogrelate at 5 mg/kg to rats for the determination of its pharmacokinetics. Following oral administration the maximum mean concentration in plasma (C(max), 11514 ng/mL) was achieved at 0.25 h (T(max)) and the area under curve (AUC0-24) was 11051 ± 3315 ng h/mL. The half-life (t(¹/2)) and clearance (Cl) were 2.9 ± 1.1 h and 490 ± 171 mL/h/kg, respectively. We believe that development of a method in rodent plasma would facilitate the ease of adaptability of sarpogrelate in human plasma.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Antagonistas do Receptor 5-HT2 de Serotonina/sangue , Succinatos/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Ratos , Ratos Wistar , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Succinatos/farmacocinética
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