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1.
J Pept Sci ; 21(6): 467-75, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25755050

RESUMO

The synthesis of a series of N-guanidinylated cyclic ureidopeptides, analogues of 1,4-ureido-deltorphin/dermorphine tetrapeptide is described. The δ- and µ-opioid receptor affinity of new guanidinylated analogues and their non-guanidinylated precursors was determined by the displacement radioligand binding experiments. Our results indicate that the guanidinylation of cyclic 1,4-ureidodeltorphin peptide analogues does not exhibit a uniform influence on the opioid receptor binding properties, similarly as reported earlier for some linear peptides. All analogues were also tested for their in vitro resistance to proteolysis during incubation with large excess of chymotrypsin, pepsin, and papain by means of mass spectroscopy. Guanidinylated ureidopeptides 1G-4G showed mixed µ agonist/δ agonist properties and high enzymatic stability indicating their potential as therapeutic agents for treatment of pain.


Assuntos
Guanidina/química , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Peptídeos Cíclicos/síntese química , Proteólise , Animais , Quimotripsina/química , Papaína/química , Pepsina A/química , Estrutura Terciária de Proteína , Ratos , Receptores Opioides delta/agonistas , Receptores Opioides delta/metabolismo , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo
2.
Eur J Med Chem ; 63: 457-67, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23523659

RESUMO

A series of novel cyclic ureidopeptides, analogues of dermorphine/deltorphine tetrapeptide, were synthesized by solid phase peptide synthesis and/or in solution. The antinociceptive activity of N-substituted amides 1-10 was evaluated using hot-plate and tail-flick tests. Analogue 1 showed significant, stronger than morphine, antinociceptive effect after systemic applications. All analogues were also tested for their in vitro resistance to proteolysis by means of mass spectroscopy and it was found that all substituted amides 1-10 showed full stability during incubation with large excess of chymotrypsin and pepsin. Compound 1 is a lead molecule for further evaluation.


Assuntos
Analgésicos Opioides/síntese química , Hiperalgesia/fisiopatologia , Oligopeptídeos/síntese química , Peptídeos Opioides/síntese química , Analgésicos Opioides/química , Analgésicos Opioides/farmacologia , Animais , Quimotripsina/metabolismo , Temperatura Alta/efeitos adversos , Hidrólise , Hiperalgesia/etiologia , Hiperalgesia/prevenção & controle , Indóis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Químicos , Estrutura Molecular , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Peptídeos Opioides/química , Peptídeos Opioides/farmacologia , Pepsina A/metabolismo , Proteólise , Espectrometria de Massas por Ionização por Electrospray , Estirenos
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