RESUMEN
BACKGROUND: Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by aggregated α-synuclein (α-syn) in oligodendrocytes and accompanied by striatonigral and olivopontocerebellar degeneration and motor symptoms. Key features of MSA are replicated in the PLP-α-syn transgenic mouse, including progressive striatonigral degeneration and motor deterioration. There are currently no approved treatments for MSA. ATH434 is a novel, orally bioavailable brain penetrant small molecule inhibitor of α-syn aggregation. OBJECTIVES: To characterize ATH434 for disease modification in a mouse model of MSA. METHODS: Six-month-old PLP-α-syn mice (MSA mice) were ATH434-treated (ATH434 in food) or untreated (normal food) for 6 months. Motor behavior and numbers of nigral and striatal neurons were evaluated. α-syn aggregates and oligomers were quantified by immunohistochemical and western blot analyses. Microglial activation and neuroinflammation were assessed by histological and molecular analyses. Ferric iron in the Substantia nigra was evaluated with the Perls method. RESULTS: ATH434-treated mice demonstrated preservation of motor performance in MSA mice that was associated with neuroprotection of nigral and striatal neurons. The rescue of the phenotype correlated with the reduction of α-syn inclusions and oligomers in animals receiving ATH434. ATH434-treated mice exhibited significantly increased lysosomal activity of microglia without increased pro-inflammatory markers, suggesting a role in α-syn clearing. ATH434-treatment was associated with lower intracellular nigral iron levels. CONCLUSIONS: Our findings demonstrate the beneficial disease-modifying effect of ATH434 in oligodendroglial α-synucleinopathy on both the motor phenotype and neurodegenerative pathology in the PLP-α-syn transgenic mouse and support the development of ATH434 for MSA. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Atrofia de Múltiples Sistemas , Animales , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , Atrofia de Múltiples Sistemas/tratamiento farmacológico , Oligodendroglía/patología , alfa-Sinucleína/genética , alfa-Sinucleína/farmacologíaRESUMEN
INTRODUCTION: The experiences of patients with mild-to-moderate haemophilia differ from those of patients with severe haemophilia or those without a bleeding disorder and include a challenging diagnosis and variability in bleeding symptoms and treatment needs. In addition, there is a significant lack of data on mild-to-moderate haemophilia, and many unmet needs remain to be identified and addressed in this group of patients. METHODS: Challenges for these patients, including women with haemophilia, were identified during a roundtable meeting attended by a group of US-based experts including healthcare professionals (e.g., physicians, nurses, and physical therapists) and patients who live with a bleeding disorder. RESULTS: Identified unmet needs included a lack of proper education on the management of their disorder and prompt treatment of bleeds, absenteeism from school and work, and challenges with personal relationships. Initiatives to assist with alleviating these unmet needs were proposed and include suggestions for healthcare professionals, haemophilia treatment centres (HTCs) and national and local organizations within the bleeding disorders community. These included HTC and community engagement programmes for patients with mild-to-moderate haemophilia, revised transition guidelines for these patients as they approach adulthood and revised diagnostic classification of mild and moderate haemophilia. Challenges unique to women with haemophilia and ways to address these issues were also discussed. CONCLUSION: This paper summarizes the challenges, initiatives and suggestions that were identified by the haemophilia experts during the roundtable meeting.
Asunto(s)
Hemofilia A , Fisioterapeutas , Adulto , Femenino , Hemofilia A/diagnóstico , Hemofilia A/terapia , Hemorragia/diagnóstico , Hemorragia/etiología , HumanosRESUMEN
AIMS: SD-1077, a selectively deuterated precursor of dopamine (DA) structurally related to L-3,4-dihydroxyphenylalanine (L-DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD-1077. METHODS: Plasma and urine PK of drug and metabolites and safety after a single oral 150 mg SD-1077 dose were compared to 150 mg L-DOPA, each in combination with 37.5 mg carbidopa (CD) in a double-blind, two-period, crossover study in healthy volunteers (n = 16). RESULTS: Geometric least squares mean ratios (GMRs) and 90% confidence intervals (90% CI) of SD-1077 vs. L-DOPA for Cmax , AUC0-t , and AUC0-inf were 88.4 (75.9-103.1), 89.5 (84.1-95.3), and 89.6 (84.2-95.4), respectively. Systemic exposure to DA was significantly higher after SD-1077/CD compared to that after L-DOPA/CD, with GMRs (90% CI) of 1.8 (1.45-2.24; P = 0.0005) and 2.06 (1.68-2.52; P < 0.0001) for Cmax and AUC0-t and a concomitant reduction in the ratio of 3,4-dihydroxyphenylacetic acid/DA confirming slower metabolic breakdown of DA by monoamine oxidase (MAO). There were increases in systemic exposures to metabolites of catechol O-methyltransferase (COMT) reaction, 3-methoxytyramine (3-MT) and 3-O-methyldopa (3-OMD) with GMRs (90% CI) for SD-1077/CD to L-DOPA/CD for 3-MT exposure of 1.33 (1.14-1.56; P = 0.0077) and 1.66 (1.42-1.93; P < 0.0001) for Cmax and AUC0-t , respectively and GMRs (90% CI) for 3-OMD of 1.19 (1.15, 1.23; P < 0.0001) and 1.31 (1.27, 1.36; P < 0.0001) for Cmax and AUC0-t . SD-1077/CD exhibited comparable tolerability and safety to L-DOPA/CD. CONCLUSIONS: SD-1077/CD demonstrated the potential to prolong exposure to central DA at comparable peripheral PK and safety to the reference L-DOPA/CD combination. A single dose of SD-1077 is safe for further clinical development in Parkinson's disease patients.
Asunto(s)
Antiparkinsonianos/farmacocinética , Carbidopa/farmacocinética , Levodopa/farmacocinética , Profármacos/farmacocinética , Administración Oral , Adulto , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/química , Área Bajo la Curva , Carbidopa/administración & dosificación , Carbidopa/efectos adversos , Estudios Cruzados , Deuterio/química , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/métodos , Femenino , Voluntarios Sanos , Humanos , Levodopa/administración & dosificación , Levodopa/efectos adversos , Levodopa/química , Masculino , Enfermedad de Parkinson/tratamiento farmacológico , Profármacos/administración & dosificación , Profármacos/efectos adversos , Profármacos/químicaRESUMEN
Corticotropin-releasing factor (CRF) receptor antagonists are under preclinical and clinical investigation for stress-related disorders. In this study the impact of receptor-ligand binding kinetics on CRF1 receptor antagonist pharmacology was investigated by measuring the association rate constant (k1), dissociation rate constant (kâ1), and kinetically derived affinity at 37°C. Three aspects of antagonist pharmacology were reevaluated: comparative binding activity of advanced compounds, in vivo efficacy, and structure-activity relationships. Twelve lead compounds, with little previously noted difference of affinity, varied substantially in their kinetic binding activity with a 510-fold range of kinetically derived affinity (kâ1/k1), 170-fold range of kâ1, and 13-fold range of k1. The kâ1 values indicated previous affinity measurements were not close to equilibrium, resulting in compression of the measured affinity range. Dissociation was exceptionally slow for three ligands (kâ1 t(1/2) of 1.6-7.2 h at 37°C). Differences of binding behavior were consistent with in vivo pharmacodynamics (suppression of adrenocorticotropin in adrenalectomized rats). Ligand concentration-effect relationships correlated with their kinetically derived affinity. Two ligands that dissociated slowly (53 and 130 min) produced prolonged suppression, whereas only transient suppression was observed with a more rapidly dissociating ligand (16 min). Investigating the structure-activity relationship indicated exceptionally low values of k1, approaching 100,000-fold less than the diffusion-limited rate. Retrospective interpretation of medicinal chemistry indicates optimizing specific elements of chemical structure overcame kinetic barriers in the association pathway, for example, constraint of the pendant aromatic orthogonal to the ligand core. Collectively, these findings demonstrate receptor binding kinetics provide new dimensions for understanding and potentially advancing the pharmacology of CRF1 receptor antagonists.
Asunto(s)
Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Animales , Unión Competitiva , Células HEK293 , Humanos , Cinética , Ligandos , Unión Proteica , Ensayo de Unión Radioligante/métodos , Ratas , Receptores de Hormona Liberadora de Corticotropina/química , Estudios Retrospectivos , Relación Estructura-ActividadRESUMEN
Converging lines of evidence suggest that AKT1 is a major mediator of the responses to insulin,insulin-like growth factor 1 (IGF1), and glucose. AKT1 also plays a key role in the regulation of both muscle cell hypertrophy and atrophy. We hypothesized that AKT1 variants may play a role in the endophenotypes that makeup metabolic syndrome. We studied a 12-kb region including the ï¬rst exon of the AKT1 gene for association with metabolic syndrome-related phenotypes in four study populations [FAMUSS cohort (n = 574; age 23.7 ± 5.7 years), Strong Heart Study (SHS) (n = 2,134; age 55.5 ± 7.9 years), Dynamics of Health, Aging and Body Composition (Health ABC) (n = 3,075; age 73.6 ± 2.9 years), and Studies of a Targeted Risk Reduction Intervention through Deï¬ned Exercise (STRRIDE)(n = 175; age 4065 years)]. We identiï¬ed a three SNP haplotype that we call H1, which represents the ancestral alleles eles at the three loci and H2, which represents the derived alleles at the three loci. In young adult European Americans (FAMUSS), H1 was associated with higher fasting glucose levels in females. In middle age Native Americans (SHS), H1 carriers showed higher fasting insulin and HOMA in males, and higher BMI in females. Inolder African-American and European American subjects(Health ABC) H1 carriers showed a higher incidence of metabolic syndrome. Homozygotes for the H1 haplotype showed about twice the risk of metabolic syndrome in both males and females (p < 0.001). In middle-aged European Americans with insulin resistance (STRRIDE) studied by intravenous glucose tolerance test (IVGTT), H1 carriers showed increased insulin resistance due to the Sg component (p = 0.021). The 12-kb haplotype is a risk factor for metabolic syndrome and insulin resistance that needs to be explored in further populations.
Asunto(s)
Síndrome Metabólico/genética , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas c-akt/genética , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento , Femenino , Humanos , Resistencia a la Insulina , Masculino , Síndrome Metabólico/etnología , Persona de Mediana Edad , Adulto JovenRESUMEN
Genome-wide association studies (GWASs) have identified polymorphic loci associated with coronary artery disease (CAD) risk factors (i.e. serum lipids) in adult populations (42-69 y). We hypothesized that younger populations would show a greater relative genetic component due to fewer confounding variables. We examined the influence of 20 GWAS loci associated with serum lipids and insulin metabolism, in a university student cohort (n = 548; mean age = 24 y), and replicated statistically associated results in a second study cohort of primary school students (n = 810, mean age = 11.5 y). Nineteen loci showed no relationship with studied risk factors in young adults. However, the ancestral allele of the rs646776 (SORT1) locus was strongly associated with increased LDL (C) in young adults [TT: 97.6 ± 1.0 mg/dL (n = 345) versus CT/CC: 87.3 ± 1.0 mg/dL (n = 203); p = 3 × 10(x6)] and children [TT: 94.0 ± 1.3 mg/dL (n = 551) versus CT/CC: 84.7 ± 1.4 mg/dL (n = 259); p = 4 × 10(x6)]. This locus is responsible for 3.6% of population variance in young adults and 2.5% of population variance in children. The effect size of the SORT1 locus is considerably higher in young populations (2.5-4.1%) compared with older subjects (1%).
Asunto(s)
LDL-Colesterol/genética , Cromosomas Humanos Par 1/genética , Enfermedad de la Arteria Coronaria/genética , Estudio de Asociación del Genoma Completo , Adulto , Niño , Diabetes Mellitus Tipo 2/genética , Ejercicio Físico , Femenino , Genotipo , Humanos , Insulina/metabolismo , Lípidos/sangre , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Adulto JovenRESUMEN
Deutetrabenazine (Austedo, Teva), an approved treatment of chorea in Huntington's disease and tardive dyskinesia in adult patients, is a rationally designed deuterated form of tetrabenazine. Two studies assessed the pharmacokinetics and safety of deutetrabenazine compared with tetrabenazine, and the effects of food on absorption of the deuterated active metabolites, α-dihydrotetrabenazine (α-HTBZ) and ß-dihydrotetrabenazine (ß-HTBZ). One study was an open-label 2-part study in healthy volunteers; the first part included a crossover single dose of two 15 mg candidate deutetrabenazine formulations in fed and fasted states compared with tetrabenazine 25 mg in the fasted state, and the second part included single and repeated dosing of the commercial formulation of deutetrabenazine (7.5, 15, and 22.5 mg) compared with tetrabenazine 25 mg. The second study was an open-label 5-way crossover study in healthy volunteers (n = 32) to evaluate relative bioavailability of 4 dose levels of the commercial formulation of deutetrabenazine (6, 12, 18, and 24 mg) with a standard meal and 18 mg with a high-fat meal. Both studies confirmed longer half-lives for active metabolites and lower peak-to-trough fluctuations for the sum of the metabolites (total [α+ß]-HTBZ) following deutetrabenazine compared with tetrabenazine (3- to 4-fold and 11-fold, respectively) in steady-state conditions. Deutetrabenazine doses estimated to provide total (α+ß)-HTBZ exposure comparable to tetrabenazine 25 mg were 11.4-13.2 mg. Food had no effect on exposure to total (α+ß)-HTBZ, as measured by AUC. Although the total (α+ß)-HTBZ Cmax of deutetrabenazine was increased by ≈50% in the presence of food, it remained lower than that of tetrabenazine.
Asunto(s)
Interacciones Alimento-Droga , Tetrabenazina/análogos & derivados , Proteínas de Transporte Vesicular de Monoaminas/antagonistas & inhibidores , Inhibidores de Captación Adrenérgica/administración & dosificación , Inhibidores de Captación Adrenérgica/efectos adversos , Inhibidores de Captación Adrenérgica/farmacocinética , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Masculino , Tetrabenazina/administración & dosificación , Tetrabenazina/efectos adversos , Tetrabenazina/farmacocinética , Adulto JovenRESUMEN
Analogs of the known H(1)-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study.
Asunto(s)
Antagonistas de los Receptores Histamínicos H1/química , Indenos/química , Piridazinas/química , Receptores Histamínicos H1/química , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Animales , Citocromo P-450 CYP2D6/metabolismo , Dimetindeno/química , Electroencefalografía , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Humanos , Indenos/farmacocinética , Indenos/uso terapéutico , Microsomas Hepáticos/metabolismo , Modelos Animales , Piridazinas/farmacocinética , Piridazinas/uso terapéutico , Ratas , Receptores Histamínicos H1/metabolismo , Relación Estructura-ActividadRESUMEN
SAR of lead benzothiophene H(1)-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H(1)-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound.
Asunto(s)
Antagonistas de los Receptores Histamínicos H1/farmacología , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Tiofenos/farmacología , Tiofenos/farmacocinética , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Humanos , Receptores Histamínicos H1/metabolismo , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/uso terapéuticoRESUMEN
RATIONALE: Sepsis-related mortality results in part from immunodeficiency secondary to profound lymphoid apoptosis. The biological mechanisms responsible are not understood. OBJECTIVES: Because recent evidence shows that platelets are involved in microvascular inflammation and that they accumulate in lymphoid microvasculature in sepsis, we hypothesized a direct role for platelets in sepsis-related lymphoid apoptosis. METHODS: We studied megakaryocytes and platelets from a murine-induced sepsis model, with validation in septic children, which showed induction of the cytotoxic serine protease granzyme B. MEASUREMENTS AND MAIN RESULTS: Platelets from septic mice induced marked apoptosis of healthy splenocytes ex vivo. Platelets from septic granzyme B null (-/-) mice showed no lymphotoxicity. CONCLUSIONS: Our findings establish a conceptual advance in sepsis: Septic megakaryocytes produce platelets with acutely altered mRNA profiles, and these platelets mediate lymphotoxicity via granzyme B. Given the contribution of lymphoid apoptosis to sepsis-related mortality, modulation of platelet granzyme B becomes an important new target for investigation and therapy.
Asunto(s)
Apoptosis , Plaquetas/metabolismo , Granzimas/metabolismo , Sepsis/metabolismo , Bazo/patología , Adolescente , Animales , Niño , Preescolar , Femenino , Granzimas/genética , Humanos , Lactante , Masculino , Megacariocitos/metabolismo , Ratones , ARN Mensajero/metabolismo , Sepsis/genética , Sepsis/patología , Índice de Severidad de la EnfermedadRESUMEN
Deutetrabenazine (Austedo, Teva Pharmaceuticals) is a deuterated form of tetrabenazine. It is the first deuterated drug to receive US regulatory approval and is approved for treatment of chorea in Huntington's disease and tardive dyskinesia. Two oral single dose studies comparing deutetrabenazine (25 mg) with tetrabenazine (25 mg) in healthy volunteers evaluated the impact of deuteration on pharmacokinetics of the active metabolites, alpha-dihydrotetrabenazine (α-HTBZ) and beta-dihydrotetrabenazine (ß-HTBZ), metabolite profile, safety, and tolerability. In the two-way, cross-over study, the mean elimination half-life of deuterated total (α + ß)-HTBZ was doubled compared with nondeuterated total (α + ß)-HTBZ, with a twofold increase in overall mean exposure (area under the concentration-time curve from zero to infinity (AUC0-inf )) and a marginal increase in mean peak plasma concentration (Cmax ). In the mass balance and metabolite profiling study, there were no novel plasma or urinary metabolites of [14 C]-deutetrabenazine relative to [14 C]-tetrabenazine. Specific deuteration in deutetrabenazine resulted in a superior pharmacokinetic profile and an increased ratio of active-to-inactive metabolites, attributes considered to provide significant benefits to patients.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacocinética , Enfermedad de Huntington/tratamiento farmacológico , Discinesia Tardía/tratamiento farmacológico , Tetrabenazina/análogos & derivados , Administración Oral , Adolescente , Inhibidores de Captación Adrenérgica/administración & dosificación , Adulto , Área Bajo la Curva , Estudios Cruzados , Femenino , Voluntarios Sanos , Humanos , Masculino , Tetrabenazina/administración & dosificación , Tetrabenazina/farmacocinética , Adulto JovenRESUMEN
INTRODUCTION: The safety of predicting conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia using apolipoprotein E (APOE) genotyping is unknown. METHODS: We randomized 114 individuals with MCI to receive estimates of 3-year risk of conversion to AD dementia informed by APOE genotyping (disclosure arm) or not (non-disclosure arm) in a non-inferiority clinical trial. Primary outcomes were anxiety and depression scores. Secondary outcomes included other psychological measures. RESULTS: Upper confidence limits for randomization arm differences were 2.3 on the State Trait Anxiety Index and 0.5 on the Geriatric Depression Scale, below non-inferiority margins of 3.3 and 1.0. Moreover, mean scores were lower in the disclosure arm than non-disclosure arm for test-related positive impact (difference: -1.9, indicating more positive feelings) and AD concern (difference: -0.3). DISCUSSION: Providing genetic information to individuals with MCI about imminent risk for AD does not increase risks of anxiety or depression and may provide psychological benefits.
RESUMEN
The benzimidazole core of the selective non-brain-penetrating H(1)-antihistamine mizolastine was used to identify a series of brain-penetrating H(1)-antihistamines for the potential treatment of insomnia. Using cassette PK studies, brain-penetrating H(1)-antihistamines were identified and in vivo efficacy was demonstrated in a rat EEG/EMG model. Further optimization focused on strategies to attenuate an identified hERG liability, leading to the discovery of 4i with a promising in vitro profile.
Asunto(s)
Bencimidazoles/antagonistas & inhibidores , Bencimidazoles/química , Encéfalo/efectos de los fármacos , Química Farmacéutica/métodos , Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/farmacología , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Animales , Diseño de Fármacos , Canal de Potasio ERG1 , Electroencefalografía/métodos , Electromiografía/métodos , Canales de Potasio Éter-A-Go-Go/química , Humanos , Modelos Químicos , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The aims of this study were to examine associations between two SNPs in the human IL-15 gene and three SNPs in the IL-15Ralpha gene with predictors of metabolic syndrome and phenotypes in muscle, strength, and bone at baseline and in response to resistance training (RT). Subjects were Caucasians who had not performed RT in the previous year and consisted of a strength cohort (n=748), volumetric cohort (n=722), and serum cohort (n=544). Subjects completed 12 weeks of unilateral RT of the non-dominant arm, using their dominant arm as an untrained control. ANCOVA analyses revealed gender-specific associations with: (1) IL-15 SNP (rs1589241) and cholesterol (p=0.04), LDL (p=0.02), the homeostasis model assessment (HOMA; p=0.03), and BMI (p=0.002); (2) IL-15 SNP (rs1057972) and the pre- to post-training absolute difference in 1RM strength (p=0.02), BMI (p=0.008), and fasting glucose (p=0.03); (3) IL-15Ralpha SNP (rs2296135) and baseline total bone volume (p=0.04) and the pre- to post-training absolute difference in isometric strength (p=0.01); and 4) IL-15Ralpha SNP (rs2228059) and serum triglycerides (p=0.04), baseline whole muscle volume (p=0.04), baseline cortical bone volume (p=0.04), and baseline muscle quality (p=0.04). All associations were consistent in showing a potential involvement of the IL-15 pathway with muscle and bone phenotypes and predictors of metabolic syndrome.
Asunto(s)
Huesos/metabolismo , Subunidad alfa del Receptor de Interleucina-15/genética , Interleucina-15/genética , Síndrome Metabólico/genética , Músculo Esquelético/metabolismo , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Femenino , Predisposición Genética a la Enfermedad , Humanos , Interleucina-15/metabolismo , Subunidad alfa del Receptor de Interleucina-15/metabolismo , Masculino , Síndrome Metabólico/metabolismo , Músculo Esquelético/anatomía & histología , Músculo Esquelético/fisiología , FenotipoRESUMEN
In vivo receptor occupancy of mGlu5 receptor antagonists was quantified in rat and mouse brain using the mGlu5 receptor selective antagonist [3H]3-methoxy-5-(pyridin-2-ylethynyl)pyridine) ([3H]methoxy-PEPy). Administration of [3H]methoxy-PEPy (50 microCi/kg i.v.) to mGlu5 receptor-deficient mice revealed binding at background levels in forebrain, whereas wild-type mice exhibited 14-fold higher binding in forebrain relative to cerebellum. Systemic administration of the mGlu5 receptor antagonists 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) reduced the binding of [3H]methoxy-PEPy in rats and mice, reflecting mGlu5 receptor occupancy by these compounds. MPEP (10 mg/kg i.p.) and MTEP (3 mg/kg i.p.) maintained >75% receptor occupancy for 2 h in rats, while in mice MPEP and MTEP achieved >75% occupancy for only 30 and 15 min, respectively. Compound levels in plasma were substantially lower in mice suggesting species differences in receptor occupancy result from differences in absorption or metabolism of the compounds. These findings demonstrate that [3H]methoxy-PEPy is useful for determining the occupancy of mGlu5 receptors in the brain.
Asunto(s)
Piridinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Sitios de Unión , Hipocampo/metabolismo , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Prosencéfalo/metabolismo , Piridinas/metabolismo , Ensayo de Unión Radioligante/métodos , Ratas , Ratas Sprague-Dawley , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/genética , Especificidad de la Especie , Tiazoles/metabolismo , Tiazoles/farmacología , Factores de Tiempo , TritioRESUMEN
Since their discovery in 1998, it has been shown that the orexin (hypocretin) peptides are involved in almost all of the functions historically associated with the lateral hypothalamus. These peptides are produced by only some thousand neurons restricted to the posterolateral hypothalamus. A decade later, the orexin neurons have emerged as an important mode of signalling in the hypothalamus. Orexins were recognized as regulators of feeding behaviour. The subsequent finding that an orexin deficiency causes narcolepsy in humans and animals indicates that these hypothalamic neuropeptides also have a crucial role in regulating sleep and wakefulness. Recent studies of orexin-producing neurons and their efferent and afferent systems, as well as phenotypic characterizations of mice with genetic alterations in the orexin system, have suggested further roles for orexin in the coordination of emotion, energy homeostasis, reward, drug addiction and arousal. In this special issue, we will discuss the role of orexins in sleep-wake regulation and its involvement in narcolepsy.
Asunto(s)
Hipotálamo/metabolismo , Péptidos y Proteínas de Señalización Intracelular/fisiología , Péptidos y Proteínas de Señalización Intracelular/uso terapéutico , Narcolepsia/metabolismo , Neuropéptidos/fisiología , Neuropéptidos/uso terapéutico , Sueño/fisiología , Vigilia/fisiología , Animales , Humanos , Narcolepsia/tratamiento farmacológico , OrexinasRESUMEN
Analogues of the known H(1)-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On the basis of overall profile, indene 1d and benzothiophene 2a had pharmacokinetic properties suitable for evaluation in night time dosing. Compound 2a did not show an in vivo cardiovascular effect from weak hERG channel inhibition.
Asunto(s)
Antagonistas de los Receptores Histamínicos H1/farmacología , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Animales , Encéfalo/metabolismo , Dimetindeno/metabolismo , Dimetindeno/farmacocinética , Dimetindeno/farmacología , Dimetindeno/uso terapéutico , Electroencefalografía/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Antagonistas de los Receptores Histamínicos H1/metabolismo , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Humanos , Ratas , Receptores Muscarínicos/metabolismo , Sueño/efectos de los fármacos , Especificidad por SustratoRESUMEN
Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.
Asunto(s)
Ciclopropanos/farmacología , Neuralgia/tratamiento farmacológico , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Dimensión del Dolor/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Estereoisomerismo , Administración Oral , Animales , Disponibilidad Biológica , Células CACO-2 , Cristalografía por Rayos X , Ciclopropanos/química , Ciclopropanos/metabolismo , Ciclopropanos/farmacocinética , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Masculino , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Milnaciprán , Modelos Moleculares , Estructura Molecular , Peso Molecular , Neuralgia/patología , Ratas , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Nervios Espinales/patología , Nervios Espinales/cirugía , Relación Estructura-ActividadRESUMEN
A novel series of 2-(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-ethylamine derivatives were designed and synthesized as GnRH receptor antagonists. SAR studies led to a series of highly active molecules against both the rat and human receptors. Furthermore, one potent compound, 17j, demonstrated dose-dependent LH suppression in castrated rats.
Asunto(s)
Piridinas/farmacología , Receptores LHRH/antagonistas & inhibidores , Animales , Células Cultivadas , Humanos , Piridinas/química , Ratas , Relación Estructura-ActividadRESUMEN
The metabotropic glutamate receptor subtype mGlu5 modulates central reward pathways. Many transmitter systems within reward pathways affect feeding. We examined the potential role of mGlu5 in body weight regulation using genetic and pharmacological approaches. Adult mice lacking mGlu5, mGluR5-/-, weighed significantly less than littermate controls (mGluR5+/+, despite no difference in ad libitum food intake. After overnight food deprivation, mGluR5-/- mice ate significantly less than their mGluR5+/+ controls when refeeding. When on a high fat diet, mGluR5-/- mice weighed less and had decreased plasma insulin and leptin concentrations. The selective mGlu5 antagonist MTEP [3-[(2-methyl-1,3-thiazol-4-yl)-ethynyl]-pyridine; 15 mg/kg s.c.] reduced refeeding after overnight food deprivation in mGluR5+/+, but not mGluR5-/- mice, demonstrating that feeding suppression is mediated via a mGlu5 mechanism. MTEP (1-10 mg/kg) decreased night-time food intake in rats in a dose-related manner. At 10 mg/kg, MTEP injected at 8.5, 4.5, or 0.5 h before refeeding reduced overnight food intake by approximately approximately 30%. Diet-induced obese (DIO) and age-matched lean rats were treated for 12 days with MTEP (3 or 10 mg/kg/day s.c.), dexfenfluramine (3 mg/kg/day s.c.), or vehicle. Daily and cumulative food intakes were reduced in DIO rats by MTEP and dexfenfluramine. Weight gain was prevented with MTEP (3 mg/kg), and weight and adiposity loss was seen with MTEP (10 mg/kg) and dexfenfluramine. Caloric efficiency was decreased, suggesting increased energy expenditure. In lean rats, similar, although smaller, effects were observed. In conclusion, using genetic and pharmacological approaches, we have shown that mGlu5 modulates food intake and energy balance in rodents.