RESUMEN
Functionally selective G protein-coupled receptor ligands are valuable tools for deciphering the roles of downstream signaling pathways that potentially contribute to therapeutic effects versus side effects. Recently, we discovered both Gi/o-biased and ß-arrestin2-biased D2 receptor agonists based on the Food and Drug Administration (FDA)-approved drug aripiprazole. In this work, based on another FDA-approved drug, cariprazine, we conducted a structure-functional selectivity relationship study and discovered compound 38 (MS1768) as a potent partial agonist that selectively activates the Gi/o pathway over ß-arrestin2. Unlike the dual D2R/D3R partial agonist cariprazine, compound 38 showed selective agonist activity for D2R over D3R. In fact, compound 38 exhibited potent antagonism of dopamine-stimulated ß-arrestin2 recruitment. In our docking studies, compound 38 directly interacts with S1935.42 on TM5 but has no interactions with extracellular loop 2, which appears to be in contrast to the binding poses of D2R ß-arrestin2-biased ligands. In in vivo studies, compound 38 showed high D2R receptor occupancy in mice and effectively inhibited phencyclidine-induced hyperlocomotion.
Asunto(s)
Agonistas de Dopamina/farmacología , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Isoquinolinas/farmacología , Compuestos de Metilurea/farmacología , Receptores de Dopamina D2/agonistas , Animales , Antipsicóticos/síntesis química , Antipsicóticos/metabolismo , Antipsicóticos/farmacología , Agonistas de Dopamina/síntesis química , Agonistas de Dopamina/metabolismo , Diseño de Fármacos , Agonismo Parcial de Drogas , Femenino , Células HEK293 , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/metabolismo , Locomoción/efectos de los fármacos , Masculino , Compuestos de Metilurea/síntesis química , Compuestos de Metilurea/metabolismo , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Estructura Molecular , Piperazinas/química , Receptores de Dopamina D2/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Arrestina beta 2/metabolismoRESUMEN
Huntington's disease (HD) symptoms are driven to a large extent by dysfunction of the basal ganglia circuitry. HD patients exhibit reduced striatal phoshodiesterase 10 (PDE10) levels. Using HD mouse models that exhibit reduced PDE10, we demonstrate the benefit of pharmacologic PDE10 inhibition to acutely correct basal ganglia circuitry deficits. PDE10 inhibition restored corticostriatal input and boosted cortically driven indirect pathway activity. Cyclic nucleotide signaling is impaired in HD models, and PDE10 loss may represent a homeostatic adaptation to maintain signaling. Elevation of both cAMP and cGMP by PDE10 inhibition was required for rescue. Phosphoproteomic profiling of striatum in response to PDE10 inhibition highlighted plausible neural substrates responsible for the improvement. Early chronic PDE10 inhibition in Q175 mice showed improvements beyond those seen with acute administration after symptom onset, including partial reversal of striatal deregulated transcripts and the prevention of the emergence of HD neurophysiological deficits. VIDEO ABSTRACT.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Enfermedad de Huntington/fisiopatología , Neostriado/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Pirazoles/farmacología , Quinolinas/farmacología , Animales , Ganglios Basales/diagnóstico por imagen , Ganglios Basales/efectos de los fármacos , Ganglios Basales/metabolismo , Ganglios Basales/fisiopatología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiopatología , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Enfermedad de Huntington/metabolismo , Ratones , Neostriado/diagnóstico por imagen , Neostriado/metabolismo , Neostriado/fisiopatología , Hidrolasas Diéster Fosfóricas , Tomografía de Emisión de Positrones , Núcleo Subtalámico/diagnóstico por imagen , Núcleo Subtalámico/efectos de los fármacos , Núcleo Subtalámico/metabolismo , Núcleo Subtalámico/fisiopatología , TritioRESUMEN
Meaningful relationships with others are often elusive for people with intellectual and developmental disabilities, but no less desired for their full inclusion and participation in society. It is well documented that people with disabilities are victims of interpersonal violence at higher rates than peers without disabilities. This article presents a formative evaluation of the Friendships and Dating Program (FDP). The FDP was designed to teach the social skills needed to develop healthy, meaningful relationships and to prevent violence in dating and partnered relationships. Thirty-one adults were recruited by 5 community agencies in Alaska to participate. The results showed the size of the participants' social networks increased and the number of incidents of interpersonal violence was reduced for participants who completed the FDP, and outcomes were maintained 10 weeks later.
Asunto(s)
Cortejo/psicología , Discapacidades del Desarrollo/psicología , Personas con Discapacidad/psicología , Amigos/psicología , Discapacidad Intelectual/psicología , Parejas Sexuales/psicología , Adulto , Femenino , Humanos , Relaciones Interpersonales , Masculino , Matrimonio/psicología , Persona de Mediana Edad , Grupo Paritario , Evaluación de Programas y Proyectos de Salud , Conducta Social , Violencia/prevención & control , Violencia/psicologíaRESUMEN
Antagonism of cannabinoid-1 (CB1) receptor signaling has been demonstrated to inhibit feeding behaviors in humans, but CB1-mediated central nervous system (CNS) side effects have halted the marketing and further development of the lead drugs against this target. However, peripherally restricted CB1 receptor antagonists may hold potential for providing the desired efficacy with reduced CNS side effect profiles. In this report we detail the discovery and structure-activity-relationship analysis of a novel bicyclic scaffold (3) that exhibits potent CB1 receptor antagonism and oral activity in preclinical feeding models. Optimization of physical properties has led to the identification of analogues which are predicted to have reduced CNS exposure and could serve as a starting point for the design of peripherally targeted CB1 receptor antagonists.
RESUMEN
Adults with intellectual and developmental disabilities are frequently abused in dating and partnered relationships. The Friendships and Dating Program (FDP) was developed to prevent violence in dating and partnered relationships and to teach social skills needed to develop healthy, meaningful relationships among this population. A pilot study indicated the FDP resulted in a statistically significant increase in social network size and a significant decrease in instances of interpersonal violence. This study focused on utilizing a Process Evaluation Model (PEM) to document the level of treatment fidelity in the delivery of the 20 session FDP for adults with intellectual and developmental disabilities delivered by community agency personnel. The PEM also documented the amount of content delivered to the participants during each session. Results indicated that direct service personnel delivered the program with a high level of fidelity. Additionally, participants engaged at high rates over the course of the 10-week program. Further, the results indicated the FDP topics and methods of delivery were appropriate for adults with intellectual and developmental disabilities. Programs should use a Process Evaluation Model (PEM) and methods as a routine quality control mechanism to assess provision of salient participant procedures.
Asunto(s)
Discapacidades del Desarrollo/psicología , Amigos/psicología , Apoyo Social , Adulto , Femenino , Humanos , Relaciones Interpersonales , Masculino , Conducta Social , Violencia/psicologíaRESUMEN
BACKGROUND: Cannabinoid 1 (CB1) receptor antagonists exhibit pharmacological properties favorable for the treatment of obesity and other related metabolic disorders. CE-178253 (1-[7-(2-Chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a]-[1,3,5]triazin-4-yl]-3-ethylaminoazetidine-3-carboxylic acid hydrochloride) is a recently discovered selective centrally-acting CB1 receptor antagonist. Despite a large body of knowledge on cannabinoid receptor antagonists little data exist on the quantitative pharmacology of this therapeutic class of drugs. The purpose of the current studies was to evaluate the quantitative pharmacology and concentration/effect relationships of CE-178253 based on unbound plasma concentration and in vitro pharmacology data in different in vivo preclinical models of FI and energy expenditure. RESULTS: In vitro, CE-178253 exhibits sub-nanomolar potency at human CB1 receptors in both binding (Ki = 0.33 nM) and functional assays (Ki = 0.07 nM). CE-178253 has low affinity (Ki > 10,000 nM) for human CB2 receptors. In vivo, CE-178253 exhibits concentration-dependent anorectic activity in both fast-induced re-feeding and spontaneous nocturnal feeding FI models. As measured by indirect calorimetry, CE-178253 acutely stimulates energy expenditure by greater than 30% in rats and shifts substrate oxidation from carbohydrate to fat as indicated by a decrease the respiratory quotient from 0.85 to 0.75. Determination of the concentration-effect relationships and ex vivo receptor occupancy in efficacy models of energy intake and expenditure suggest that a greater than a 2-fold coverage of the Ki (50-75% receptor occupancy) is required for maximum efficacy. Finally, in two preclinical models of obesity, CE-178253 dose-dependently promotes weight loss in diet-induced obese rats and mice. CONCLUSIONS: We have combined quantitative pharmacology and ex vivo CB1 receptor occupancy data to assess concentration/effect relationships in food intake, energy expenditure and weight loss studies. Quantitative pharmacology studies provide a strong a foundation for establishing and improving confidence in mechanism as well as aiding in the progression of compounds from preclinical pharmacology to clinical development.
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Depresores del Apetito/farmacología , Depresores del Apetito/uso terapéutico , Azetidinas/farmacología , Azetidinas/uso terapéutico , Obesidad/tratamiento farmacológico , Receptor Cannabinoide CB1/antagonistas & inhibidores , Triazinas/farmacología , Triazinas/uso terapéutico , Pérdida de Peso/efectos de los fármacos , Animales , Depresores del Apetito/metabolismo , Depresores del Apetito/farmacocinética , Azetidinas/metabolismo , Azetidinas/farmacocinética , Unión Competitiva , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/sangre , Obesidad/metabolismo , Consumo de Oxígeno/efectos de los fármacos , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/antagonistas & inhibidores , Receptor Cannabinoide CB2/genética , Receptor Cannabinoide CB2/metabolismo , Triazinas/metabolismo , Triazinas/farmacocinéticaRESUMEN
We report the synthesis of a series of [3.2.1]azabicyclic biaryl ethers as selective agonists of alpha3- and alpha6-containing nicotinic receptors. In particular, compound 17a from this series is a potent alpha3beta4 and alpha6/4beta4 receptor agonist in terms of both binding and functional activity. Compound 17a also shows potent in vivo activity in CNS-mediated animal models that are sensitive to antipsychotic drugs. Compound 17a may thus be a useful tool for studying the role of alpha3beta4 and alpha6/4beta4 nicotinic receptors in CNS pharmacology.
Asunto(s)
Compuestos de Azabiciclo/química , Agonistas Nicotínicos/química , Receptores Nicotínicos/química , Sulfonamidas/química , Compuestos de Azabiciclo/síntesis química , Compuestos de Azabiciclo/farmacología , Agonistas Nicotínicos/síntesis química , Agonistas Nicotínicos/farmacología , Receptores Nicotínicos/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacologíaRESUMEN
Romantic relationships are important in the lives of adults with developmental disabilities. The purpose of this study was to explore dating and romantic relationships among these adults and to identify the nature and extent of interpersonal violence in their relationships. A random sample of 47 women and men participated in semistructured interviews. The authors found that relationships sounded very typical of people without disabilities, but their time together was more limited than they wanted. A high percentage of participants had experienced interpersonal violence, primarily in the form of name calling, yelling, screaming, and physical assault. Although the police and family or friends were the first sources of assistance following an abusive incident, more than one third of the participants said they did not seek any help.
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Cortejo , Discapacidad Intelectual/psicología , Amor , Violencia/psicología , Adolescente , Adulto , Femenino , Humanos , Vida Independiente/psicología , Discapacidad Intelectual/epidemiología , Entrevista Psicológica , Actividades Recreativas , Masculino , Persona de Mediana Edad , Policia , Violación/psicología , Violación/estadística & datos numéricos , Factores de Riesgo , Delitos Sexuales/psicología , Delitos Sexuales/estadística & datos numéricos , Conducta Social , Violencia/estadística & datos numéricos , Heridas y Lesiones , Adulto JovenRESUMEN
We describe a novel series of inhibitors of the type 1 glycine transporter (GlyT1) as an approach to relieving the glutamatergic deficit that is thought to underlie schizophrenia. Synthesis and SAR follow-up of a series of octahydro-cyclopenta[c]pyrrole derivatives afforded potent in vitro inhibition of GlyT1 as well as in vivo activity in elevating CSF glycine. We also found that a 3-O(c-pentyl), 4-F substituent may serve as a surrogate for the widely used 3-trifluoromethoxy group, suggesting its application as an isostere for future medicinal chemistry studies.
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Ciclopentanos/química , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Pirroles/química , Animales , Línea Celular , Ciclopentanos/farmacología , Perros , Proteínas de Transporte de Glicina en la Membrana Plasmática/fisiología , Humanos , Microsomas/efectos de los fármacos , Microsomas/fisiología , Pirroles/farmacologíaRESUMEN
A series of conformationally constrained bicyclic derivatives derived from SR141716 was prepared and evaluated as hCB(1)-R antagonists and inverse agonists. Optimization of the structure-activity relationships around the 2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one derivative 2a led to the identification of two compounds with oral activity in rodent feeding models (2h and 4a). Replacement of the PP group in 2h with other bicyclic groups resulted in a loss of binding affinity.
Asunto(s)
Analgésicos/síntesis química , Analgésicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Conducta Alimentaria/efectos de los fármacos , Receptor Cannabinoide CB1/antagonistas & inhibidores , Animales , Sitios de Unión , Conducta Alimentaria/fisiología , Modelos Biológicos , Piperidinas/química , Pirazoles/química , Pirazolonas/química , Pirimidinonas/química , Receptor Cannabinoide CB1/agonistas , Rimonabant , Roedores , Relación Estructura-ActividadRESUMEN
Treatment with the atypical antipsychotics olanzapine and clozapine has been associated with an increased risk for deterioration of glucose homeostasis, leading to hyperglycemia, ketoacidosis, and diabetes, in some cases independent of weight gain. Because these events may be a consequence of their ability to directly alter insulin secretion from pancreatic beta-cells, we determined the effects of several antipsychotics on cholinergic- and glucose-stimulated insulin secretion from isolated rat islets. At concentrations encompassing therapeutically relevant levels, olanzapine and clozapine reduced insulin secretion stimulated by 10 micromol/l carbachol plus 7 mmol/l glucose. This inhibition of insulin secretion was paralleled by significant reductions in carbachol-potentiated inositol phosphate accumulation. In contrast, risperidone or ziprasidone had no adverse effect on cholinergic-induced insulin secretion or inositol phosphate accumulation. None of the compounds tested impaired the islet secretory responses to 8 mmol/l glucose alone. Finally, in vitro binding and functional data show that olanzapine and clozapine (unlike risperidone, ziprasidone, and haloperidol) are potent muscarinic M3 antagonists. These findings demonstrate that low concentrations of olanzapine and clozapine can markedly and selectively impair cholinergic-stimulated insulin secretion by blocking muscarinic M3 receptors, which could be one of the contributing factors to their higher risk for producing hyperglycemia and diabetes in humans.
Asunto(s)
Antipsicóticos/farmacología , Carbacol/farmacología , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Antagonistas Muscarínicos/farmacología , Animales , Benzodiazepinas/farmacología , Carbacol/antagonistas & inhibidores , Clozapina/farmacología , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Cinética , Masculino , Olanzapina , Ratas , Ratas Sprague-DawleyRESUMEN
Olanzapine and clozapine produce robust increases in hippocampal acetylcholine release during acetylcholinesterase inhibition, while other antipsychotics, including thioridazine, have only small effects. Since thioridazine binds with similar high affinities to muscarinic receptors as olanzapine and clozapine, muscarinic autoreceptor blockade was ruled out as a primary mechanism [Neuropsychopharmacology 26 (2002) 583]. This study compared in vitro binding affinities and functional activities of olanzapine, clozapine, thioridazine, ziprasidone, risperidone, chlorpromazine and scopolamine at muscarinic M2 receptors with their in vivo potencies to increase acetylcholine release in the rat hippocampus. We found that scopolamine, olanzapine and clozapine, but also high doses of thioridazine and chlorpromazine, markedly increase acetylcholine release. The reduced in vivo potencies of thioridazine and chlorpromazine are consistent with their significantly weaker functional antagonist activity at human muscarinic M2 receptors, while thioridazine's reduced binding affinity for rat muscarinic M2 receptors and lower brain exposure, may further contribute to its weak in vivo potency compared to olanzapine. The excellent correlation between in vitro antagonist activities of antipsychotics at muscarinic M2 receptors and their in vivo potencies to increase acetylcholine release, suggests that olanzapine, clozapine, as well as thioridazine and chlorpromazine, increase acetylcholine release via blockade of terminal muscarinic M2 autoreceptors.
Asunto(s)
Acetilcolina/metabolismo , Antipsicóticos/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Antagonistas Muscarínicos/farmacología , Receptores Muscarínicos/fisiología , Animales , Células CHO , Cricetinae , Humanos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The synthesis and nNOS and eNOS activity of 6-(4-(dimethylaminoalkyl)-/6-(4-(dimethylaminoalkoxy)-5-ethyl-2-methoxyphenyl)-pyridin-2-ylamines and 6-(4-(dimethylaminoalkyl)-/6-(4-(dimethylaminoalkoxy)-2,5-dimethoxyphenyl)-pyridin-2-ylamines 1-8 are described. These compounds are potent inhibitors of the human nNOS isoform.