RESUMEN
κ-Opioid receptor agonists with high selectivity over the µ-opioid receptor and peripheral selectivity are attractive targets in the development of drugs for pain. We have previously attempted to create novel analgesics with peripheral selective κ-opioid receptor agonist on the basis of TRK-820. In this study, we elucidated the biological properties of 17-hydroxy-cyclopropylmethyl and 10α-hydroxy derivatives. These compounds were found to have better κ-opioid receptor selectivity and peripheral selectivity than TRK-820.
Asunto(s)
Analgésicos/farmacología , Descubrimiento de Drogas , Morfinanos/farmacología , Dolor/tratamiento farmacológico , Receptores Opioides kappa/agonistas , Compuestos de Espiro/farmacología , Ácido Acético , Analgésicos/síntesis química , Analgésicos/química , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos ICR , Modelos Moleculares , Conformación Molecular , Morfinanos/síntesis química , Morfinanos/química , Dolor/inducido químicamente , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
This Letter describes the identification of a series of novel non-acetylenic mGluR5 negative allosteric modulators based on the alpha-substituted acylamine structure. An initial structure-activity relationship study suggested that (R)-19b and (R)-19j might have good in vitro activity. When administered orally, these compounds were found to have an anxiolytic-like effect in a mouse model of stress-induced hyperthermia.
Asunto(s)
Aminas/química , Ansiolíticos/síntesis química , Receptor del Glutamato Metabotropico 5/química , Administración Oral , Regulación Alostérica , Aminas/síntesis química , Aminas/farmacología , Animales , Ansiolíticos/química , Ansiolíticos/farmacología , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Hipertermia Inducida , Ratones , Conformación Molecular , Receptor del Glutamato Metabotropico 5/metabolismo , Recto/efectos de los fármacos , Recto/fisiología , Estereoisomerismo , Relación Estructura-Actividad , TemperaturaRESUMEN
An efficient and straightforward synthesis of a novel m-phenylene derivative has been developed. The optically pure dibromo compound was selected as a starting material. Through a protocol involving the Prins reaction and two steps of the Horner-Wadsworth-Emmons reaction, the basic skeleton was constructed with appropriate alpha and omega side chains. The compound proved to be a highly selective EP(4) agonist and a possible drug candidate for maturation of the uterine cervix.
Asunto(s)
Benzofuranos/síntesis química , Benzofuranos/farmacología , Folículo Ovárico/efectos de los fármacos , Subtipo EP4 de Receptores de Prostaglandina E/agonistas , Animales , Benzofuranos/química , Cuello del Útero/crecimiento & desarrollo , Femenino , Cobayas , Folículo Ovárico/crecimiento & desarrollo , Conejos , Subtipo EP4 de Receptores de Prostaglandina E/metabolismoRESUMEN
Novel series of 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides and 3-amino-N-(4-aryltetrahydropyran-4-yl)butanamides were synthesized and evaluated as dipeptidyl peptidase IV (DPP-IV) inhibitors. Derivatives incorporating the 6-substituted benzothiazole group showed highly potent DPP-IV inhibitory activity. Oral administration of (3R)-3-amino-4-(2,4,5-trifluorophenyl)-N-{4-[6-(2-methoxyethoxy)benzothiazol-2-yl]tetrahydropyran-4-yl}butanamide (12u) reduced blood glucose excursion in an oral glucose tolerance test.