RESUMO
All sixteen stereoisomeric analogues of endomorphin-2 (H-Tyr-Pro-Phe-Phe-NH(2)) were synthesized by Fmoc-strategy using solid phase methods. Although synthetic endomorphin-2 exhibited similar mu- and delta-opioid receptor-binding activity to the natural compound, endomorphin-2 analogues containing d-amino acid isomers exhibited lower interaction with mu-receptors depending on the particular combination. The data clearly indicated that the three dimensional structure of endomorphin-2 with the natural l-configuration was the most suitable for binding within the mu receptor, but specific residues are important for activity. Circular dichroism studies verified that changes in chirality of amino acids in the endomorphin-2 sequence resulted in structural conformation. These alterations significantly reduced the specificity for mu-receptor-binding sites.
Assuntos
Oligopeptídeos/química , Receptores Opioides/química , Animais , Oligopeptídeos/síntese química , Oligopeptídeos/metabolismo , Ligação Proteica , Conformação Proteica , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores Opioides/metabolismo , EstereoisomerismoRESUMO
Pseudo-peptide analogs of trans-4-aminomethylcyclohexanecarbonyl-L-phenylalanyl-4-aminopheny l acetic acid (PKSI-527, plasma kallikrein selective inhibitor), in which an amide bond (peptide bond) has been replaced by a CH2-NH bond, i.e., trans-4-aminomethylcyclohexanecarbonyl-L-phenylalanyl-psi (CH2-NH)-4-aminophenyl acetic acid (I), trans-4-aminomethylcyclohexanecarbonyl-psi (CH2-NH)-L-phenylalanyl-4-aminophenyl acetic acid (II) and trans-4-aminomethylcyclohexanecarbonyl-D-phenylalanyl-psi (CH2-NH)-4-aminophenyl acetic acid (III) were synthesized. These pseudo-peptide analogs did not exhibit any detectable inhibitory activity against plasma kallikrein (PK), plasmin (PL), urokinase (UK), thrombine (TH) or trypsin (TRY). These results indicate that both carbonyl groups in the PKSI-527 are important for the manifestation of potent inhibitory activity against plasma kallikrein.
Assuntos
Calicreínas/antagonistas & inibidores , Fenilalanina/análogos & derivados , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacologia , Ácido Tranexâmico/análogos & derivados , Animais , Fibrinolisina/antagonistas & inibidores , Fibrinolíticos/síntese química , Fibrinolíticos/farmacologia , Humanos , Calicreínas/metabolismo , Fenilalanina/química , Fenilalanina/farmacologia , Ativadores de Plasminogênio/antagonistas & inibidores , Trombina/antagonistas & inibidores , Ácido Tranexâmico/química , Ácido Tranexâmico/farmacologia , Inibidores da Tripsina/farmacologia , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidoresRESUMO
Cyclization of dipeptidyl chloromethyl ketones gave 6-(4-aminobutyl)-3-carboxyethyl-5-methyl-2(1H)-pyrazinone, 3-(4-aminobutyl)-6-carboxyethyl-5-methyl-2(1H)-pyrazinone, and 3,6-bis(4-aminobutyl)-5-methyl-2(1H)-pyrazinone, which were inserted into the enkephalin sequence to give opioid mimetics. Thus, it was confirmed that a pyrazinone ring can be easily inserted into a peptide sequence in order to evaluate structural components required for biologically active peptides.