RESUMEN
Glutamate is a major neurotransmitter in the central nervous system, and abnormal glutamate neurotransmission has been implicated in many neurological disorders, including schizophrenia, Alzheimer's disease, Parkinson's disease, addiction, anxiety, depression, epilepsy, and pain. Metabotropic glutamate receptors (mGluRs) activate intracellular signaling cascades in a G protein-dependent manner, which offer the opportunity for developing drugs that regulate glutamate neurotransmission in a functionally selective manner. In the present study, we further characterize the human mGluR2 (hmGluR2) potentiator binding site by showing that the substitution of the three amino acids found to be required for hmGluR2 potentiation, specifically Ser(688), Gly(689), and Asn(735), with the homologous hmGluR3 amino acids, inactivates the positive allosteric modulator activity of several structurally unique mGluR2 potentiators. Based on the characterization of the hmGluR2 potentiator binding site, we developed a novel scintillation proximity assay that was able to discriminate between compounds that were hmGluR2-specific potentiators, and those that were active on both hmGluR2 and hmGluR3. In addition, we substituted Ser(688), Gly(689), and Asn(735) into hmGluR3 and created an active hmGluR2 allosteric modulation site on the hmGluR3 receptor.
Asunto(s)
Sitio Alostérico/genética , Aminoácidos/metabolismo , Receptores de Glutamato Metabotrópico/química , Receptores de Glutamato Metabotrópico/genética , Regulación Alostérica/genética , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Aminoácidos/química , Aminoácidos/genética , Animales , Línea Celular , Células Cultivadas , Humanos , Masculino , Datos de Secuencia Molecular , Mutación Puntual , Unión Proteica/genética , Ratas , Ratas Sprague-DawleyRESUMEN
Metabotropic glutamate receptor 2 (mGluR2) has been implicated in a variety of CNS disorders, including schizophrenia. Disclosed herein is the development of a new series of allosteric potentiators of mGluR2. Structure-activity relationship studies in conjunction with pharmacokinetic data led to the discovery of indole 5, which is active in an animal model for schizophrenia.
Asunto(s)
Acetofenonas/farmacología , Modelos Animales de Enfermedad , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Acetofenonas/química , Acetofenonas/farmacocinética , Regulación Alostérica/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Reactivos de Enlaces Cruzados/química , Humanos , Ketamina/farmacología , Estructura Molecular , Ratas , Esquizofrenia/inducido químicamente , Relación Estructura-ActividadRESUMEN
A novel series of substituted 3-phenyl benzoylpyrazoles were prepared and tested as potential grass herbicides. The targeted materials were prepared by three newly developed synthetic routes, which allowed a comprehensive study of the SAR (structure-activity relationships) of this series. The best combination of grass weed activity (Avena fatua L, Setaria viridis (L) Beauv and Alopecurus myosuroides Huds) and wheat selectivity was obtained with an alkoxy group in the 4-position of the phenyl ring. Activity was further enhanced by the presence of tert-butyl on the pyrazole and a methyl group at the C-2 position of the benzoyl moiety. The alkoxy-substituted 3-phenylbenzoylpyrazoles are a novel class of herbicides with potential utility for control of important grass weeds in cereals.
