ABSTRACT
The synthesis of a Ni-nitrilotriacetic acid (Ni-NTA) attached via a new tyrosine-based linker matrix on monolithic crosslinked poly(vinyl benzyl chloride)/poly(vinylpyrrolidinone) is described. This matrix is incorporated inside a microstructured PASSflow reactor which was used for automatic purification and immobilisation of His(6)-tagged proteins. These could be used as stable and highly active biocatalysts for the synthesis of (R)-benzoin (6), (R)-2-hydroxy-1-phenylpropan-1-one (7) and 6-O-acetyl-D-glucal (17) in a flow-through mode.
Subject(s)
Aldehyde-Lyases/isolation & purification , Bioreactors , Escherichia coli/enzymology , Nickel/metabolism , Nitrilotriacetic Acid/metabolism , Povidone/metabolism , Tyrosine/metabolism , Benzoin/chemistry , Benzoin/metabolism , Catalysis , Enzymes, Immobilized/metabolism , Esters/metabolism , Hydrolysis , Lysine/metabolism , StereoisomerismABSTRACT
(4-Benzylpiperidine-1-yl)-(6-hydroxy-1H-indole-2-yl)-methanone (6a) derived from (E)-1-(4-benzylpiperidin-1-yl)-3-(4-hydroxy-phenyl)-propenone (5) was identified as a potent NR2B subunit-selective antagonist of the NMDA receptor. To establish the structure-activity relationship (SAR) and to attempt the improvement of the ADME properties of the lead, a series of compounds were prepared and tested. Several derivatives showed low nanomolar activity both in the binding and in the functional assay. In a formalin-induced hyperalgesia model in mice, 6a and (4-benzylpiperidine-1-yl)-[5(6)-hydroxy-1H-benzimidazol-2-yl]-methanone (60a) were as active as besonprodil (2) after oral administration. A CoMSIA model was developed based on binding data of a series of indole- and benzimidazole-2-carboxamides.
Subject(s)
Analgesics/chemical synthesis , Benzimidazoles/chemical synthesis , Indoles/chemical synthesis , Piperazines/chemical synthesis , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Analgesics/chemistry , Analgesics/pharmacology , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Calcium/metabolism , Cells, Cultured , In Vitro Techniques , Indoles/chemistry , Indoles/pharmacology , Intracellular Space/metabolism , Male , Mice , Models, Molecular , Pain Measurement , Patch-Clamp Techniques , Piperazines/chemistry , Piperazines/pharmacology , Prosencephalon/cytology , Prosencephalon/metabolism , Quantitative Structure-Activity Relationship , Radioligand Assay , Rats , Rats, WistarABSTRACT
A novel series of oxamides derived from indole-2-carboxamides was identified as potent NR2B selective NMDA receptor antagonists. Several members of this group showed good analgesic activity in the mouse formalin test.
Subject(s)
Indoles/chemical synthesis , Indoles/pharmacology , N-Methylaspartate/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Mice , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
A novel series of indole-2-carboxamide derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of the number and position of OH groups on the indole skeleton as well as the substitution of the piperidine ring on the biological activity of the compounds was studied.