RESUMEN
Rett syndrome (RS) is a neurodevelopmental disorder that shares many symptomatic and pathological commonalities with idiopathic autism. Alterations in protein synthesis-dependent synaptic plasticity (PSDSP) are a hallmark of a number of syndromic forms of autism; in the present work, we explore the consequences of disruption and rescue of PSDSP in a mouse model of RS. We report that expression of a key regulator of synaptic protein synthesis, the metabotropic glutamate receptor 5 (mGlu5) protein, is significantly reduced in both the brains of RS model mice and in the motor cortex of human RS autopsy samples. Furthermore, we demonstrate that reduced mGlu5 expression correlates with attenuated DHPG-induced long-term depression in the hippocampus of RS model mice, and that administration of a novel mGlu5 positive allosteric modulator (PAM), termed VU0462807, can rescue synaptic plasticity defects. Additionally, treatment of Mecp2-deficient mice with VU0462807 improves motor performance (open-field behavior and gait dynamics), corrects repetitive clasping behavior, as well as normalizes cued fear-conditioning defects. Importantly, due to the rationale drug discovery approach used in its development, our novel mGlu5 PAM improves RS phenotypes and synaptic plasticity defects without evoking the overt adverse effects commonly associated with potentiation of mGlu5 signaling (i.e. seizures), or affecting cardiorespiratory defects in RS model mice. These findings provide strong support for the continued development of mGlu5 PAMs as potential therapeutic agents for use in RS, and, more broadly, for utility in idiopathic autism.
Asunto(s)
Trastorno Autístico/genética , Receptor del Glutamato Metabotropico 5/genética , Síndrome de Rett/genética , Convulsiones/genética , Adulto , Regulación Alostérica/genética , Animales , Trastorno Autístico/tratamiento farmacológico , Trastorno Autístico/patología , Autopsia , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/patología , Humanos , Masculino , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones Noqueados , Corteza Motora/efectos de los fármacos , Corteza Motora/patología , Plasticidad Neuronal/efectos de los fármacos , Pirazoles/administración & dosificación , Pirimidinonas/administración & dosificación , Receptor del Glutamato Metabotropico 5/biosíntesis , Síndrome de Rett/tratamiento farmacológico , Síndrome de Rett/patología , Convulsiones/tratamiento farmacológico , Convulsiones/patología , Transducción de Señal/efectos de los fármacos , Adulto JovenRESUMEN
Allosteric modulation of G protein-coupled receptors has gained considerable attention in the drug discovery arena because it opens avenues to achieve greater selectivity over orthosteric ligands. We recently identified a series of positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu(5)) for the treatment of schizophrenia that exhibited robust heterotropic activation of CYP3A4 enzymatic activity. The prototypical compound from this series, 5-(4-fluorobenzyl)-2-((3-fluorophenoxy)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (VU0448187), was found to activate CYP3A4 to >100% of its baseline intrinsic midazolam (MDZ) hydroxylase activity in vitro; activation was CYP3A substrate specific and mGlu(5) PAM dependent. Additional studies revealed the concentration-dependence of CYP3A activation by VU0448187 in multispecies hepatic and intestinal microsomes and hepatocytes, as well as a diminished effect observed in the presence of ketoconazole. Kinetic analyses of the effect of VU0448187 on MDZ metabolism in recombinant P450 or human liver microsomes resulted in a significant increase in V(max) (minimal change in K(m)) and required the presence of cytochrome b5. The atypical kinetics translated in vivo, as rats receiving an intraperitoneal administration of VU0448187 prior to MDZ treatment demonstrated a significant increase in circulating 1- and 4-hydroxy- midazolam (1-OH-MDZ, 4-OH-MDZ) levels compared with rats administered MDZ alone. The discovery of a potent substrate-selective activator of rodent CYP3A with an in vitro to in vivo translation serves to illuminate the impact of increasing intrinsic enzymatic activity of hepatic and extrahepatic CYP3A in rodents, and presents the basis to build models capable of framing the clinical relevance of substrate-dependent heterotropic activation.
Asunto(s)
Regulación Alostérica/fisiología , Interacciones Farmacológicas/fisiología , Hígado/enzimología , Hígado/metabolismo , Midazolam/metabolismo , Oxigenasas de Función Mixta/metabolismo , Animales , Citocromo P-450 CYP3A/metabolismo , Hepatocitos/enzimología , Hepatocitos/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Intestinos/enzimología , Cetoconazol/metabolismo , Cinética , Masculino , Ratones , Microsomas/enzimología , Microsomas/metabolismo , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Herein we report the discovery and SAR of a novel series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on an aryl glycine sulfonamide scaffold. This series represents a rare non-MPEP site mGlu(5) PAM chemotype.
Asunto(s)
Descubrimiento de Drogas , Glicina/farmacología , Receptores de Glutamato Metabotrópico/metabolismo , Sulfonamidas/farmacología , Regulación Alostérica/efectos de los fármacos , Animales , Sitios de Unión/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Glicina/análogos & derivados , Glicina/química , Humanos , Modelos Moleculares , Estructura Molecular , Ratas , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on a simple acyclic ether series. Modifications led to a gain of MPEP site interaction through incorporation of a chiral amide in conjunction with a nicotinamide core. A highly potent PAM, 8v (VU0404251), was shown to be efficacious in a rodent model of psychosis. These studies suggest that potent PAMs within topologically similar chemotypes can be developed to preferentially interact or not interact with the MPEP allosteric binding site.
Asunto(s)
Regulación Alostérica/efectos de los fármacos , Antipsicóticos/química , Antipsicóticos/farmacología , Niacinamida/química , Niacinamida/farmacología , Receptores de Glutamato Metabotrópico/metabolismo , Sitio Alostérico/efectos de los fármacos , Animales , Antipsicóticos/uso terapéutico , Éteres/química , Éteres/farmacología , Éteres/uso terapéutico , Humanos , Niacinamida/uso terapéutico , Trastornos Psicóticos/tratamiento farmacológico , Ratas , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/química , Relación Estructura-ActividadRESUMEN
A novel series of cis-fused 2-N,N-dimethylaminomethyl-2,3,3a,12b-tetrahydrodibenzo[b,f]furo[2,3-d]oxepin derivatives modified at position C-11 was prepared and evaluated for its potential antidepressant/anxiolytic properties. In vitro affinities for the norepinephrine transporter and for 5-HT(2A) and 5-HT(2C) receptors, as well as the ED(50) values obtained in some in vivo assays predictive for antidepressant and anxiolytic potential are reported.