RESUMO
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.
Assuntos
Analgésicos/farmacologia , Descoberta de Drogas , Morfinanos/farmacologia , Dor/tratamento farmacológico , Receptores Opioides kappa/agonistas , Compostos de Espiro/farmacologia , Ácido Acético , Analgésicos/síntese química , Analgésicos/química , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Conformação Molecular , Morfinanos/síntese química , Morfinanos/química , Dor/induzido quimicamente , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Aminas/química , Ansiolíticos/síntese química , Receptor de Glutamato Metabotrópico 5/química , Administração Oral , Regulação Alostérica , Aminas/síntese química , Aminas/farmacologia , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Cristalografia por Raios X , Modelos Animais de Doenças , Hipertermia Induzida , Camundongos , Conformação Molecular , Receptor de Glutamato Metabotrópico 5/metabolismo , Reto/efeitos dos fármacos , Reto/fisiologia , Estereoisomerismo , Relação Estrutura-Atividade , TemperaturaRESUMO
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.
Assuntos
Benzofuranos/síntese química , Benzofuranos/farmacologia , Folículo Ovariano/efeitos dos fármacos , Receptores de Prostaglandina E Subtipo EP4/agonistas , Animais , Benzofuranos/química , Colo do Útero/crescimento & desenvolvimento , Feminino , Cobaias , Folículo Ovariano/crescimento & desenvolvimento , Coelhos , Receptores de Prostaglandina E Subtipo EP4/metabolismoRESUMO
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.