RESUMO
A series of 5-phenyl-3-ureidobenzodiazepine-2,4-diones was synthesized and evaluated as cholecystokinin-B (CCK-B) receptor antagonists. Structure-activity relationship (SAR) studies revealed the importance of the N-1 substituent for potent and selective CCK-B affinity. Addition of substituents at the urea side chain provided in some cases more potent compounds. Moreover the introduction of bulky substituents such as adamantylmethyl at N-1 and resolution of the racemic ureas resulted in our lead compound GV150013.
Assuntos
Ansiolíticos/síntese química , Benzodiazepinas/síntese química , Receptores da Colecistocinina/antagonistas & inibidores , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Callithrix , Córtex Cerebral/metabolismo , Cristalografia por Raios X , Cobaias , Células HeLa , Humanos , Técnicas In Vitro , Membranas , Camundongos , Modelos Moleculares , Pâncreas/metabolismo , Ensaio Radioligante , Ratos , Receptor de Colecistocinina A , Receptor de Colecistocinina B , Receptores da Colecistocinina/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The presence of a chain bearing a stereogenic centre at the N-5 position of 1-(1-adamantylmethyl)-3-arylureido-2,4-dioxo-1,5-benzodiazep ines induces optical resolution. The synthesis of these compounds and their potency as potential CCK-B receptor antagonists is discussed briefly here.
Assuntos
Benzodiazepinas/síntese química , Receptores da Colecistocinina/antagonistas & inibidores , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Receptor de Colecistocinina B , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A liquid chromatographic (LC) method for the analysis of erythromycin and related substances has been adapted from an isocratic method developed by Chepkwony et al. (2001). The suitability of the method for general application as a compendial (pharmacopoeia) method has been assessed by means of an interlaboratory (collaborative) study. The method involves LC separation on a XTerra C18 column kept at 65 degrees C and UV detection at 210 nm. Five laboratories, located in Europe and the United States (US), participated in the study. Four erythromycin samples were tested. The main components (erythromycin A (EA), erythromycin B (EB), erythromycin C (EC)) and the impurities were determined. The analysis of variance was carried out on the results of the five laboratories to evaluate the between-laboratory consistencies and the laboratory-sample interaction. The estimates for the repeatability and reproducibility of the method, expressed as relative standard deviation (RSD) of the result of the determination of EA, were calculated to be 0.8% and 1.4% respectively. It is concluded that the method examined is a good replacement for the methods currently described in the European Pharmacopoeia (Ph. Eur.) and the United States Pharmacopoeia (USP), especially for its enhanced selectivity.
Assuntos
Cromatografia Líquida/métodos , Eritromicina/análise , Espectrofotometria Ultravioleta/métodos , Comportamento Cooperativo , Contaminação de Medicamentos/prevenção & controle , Europa (Continente) , Estrutura Molecular , Farmacopeias como Assunto , Reprodutibilidade dos Testes , Estados UnidosRESUMO
A series of 3,8-diazabicyclo (3.2.1) octanes (DBO) (1) substituted at the nitrogen atoms by acyl and aralkenyl groups, were tested in in vitro binding assays towards mu and delta opioid receptors. The most representative terms (1a, 1d, 1g, 1j,) were also evaluated for the analgesic potency in vivo by the hot plate method. Among the compounds tested the most potent was the p.nitrocinnamyl DBO (1d) which displayed a mu/delta selectivity and an analgesic activity respectively 25 and 17 fold those of morphine. On the contrary, the m.hydroxycinnamyl DBO (1g) was markedly less active as agonist than the parent 1a, thus suggesting that structure 1 interacts with opioid receptors in a different fashion than morphine. Compound 1j isomer of 1a which is provided with high mu affinity, but lower analgesic potency, was found to possess a mixed agonist-antagonist activity.
Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Entorpecentes/farmacologia , Octanos/farmacologia , Receptores Opioides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Compostos Bicíclicos com Pontes/metabolismo , Técnicas In Vitro , Masculino , Camundongos , Conformação Molecular , Morfina/farmacologia , Octanos/metabolismo , Receptores Opioides delta , Receptores Opioides mu , Fatores de TempoRESUMO
The synthesis and biological evaluation of 3-ureido and 3-carbamate derivatives of 1,5-benzodiazepines bearing bridged cycloalkyl substituents at N-1 are reported. Their activity as CCK-B receptor ligands is briefly discussed.