RESUMO
A conformational analysis of peptides having dipropylglycine (Dpg) or 1-aminocycloheptanecarboxylic acid (Ac7 c) within l-leucine (Leu) residues was conducted in solution and in a crystal state. Dpg and Ac7 c had similar structures with acyclic and cyclic side chains, respectively. FTIR, 1 H NMR, and CD spectra measurements revealed that the preferred conformations of Dpg- and Ac7 c-containing l-Leu peptides in solution were similar; both had a right-handed (P) 310 -helix. The Dpg-containing octapeptide adopted a right-handed (P) α-helix in the crystal state. Dpg and Ac7 c homopeptides had planar and helical structures as their preferred conformations, respectively; however, Dpg- and Ac7 c-containing l-Leu peptides adopted similar structures in solution. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 210-218, 2016.
RESUMO
In investigating potent sodium (Na(+)) channel blockers for the treatment of ischemic stroke, we synthesized a novel series of 3-amino-1-(5-indanyloxy)-2-propanol derivatives and evaluated their inhibitory effects on neuronal Na(+) channels. The 3-amino-1-(5-indanyloxy)-2-propanol derivatives exhibited potent blocking activity for Na(+) channels and a significantly low affinity for dopamine D(2) receptors, which demonstrates a minimal clinical risk for extrapyramidal side effects. In particular, compound 4b, a 3-amino-1-(5-indanyloxy)-2-propanol derivative bearing a benzimidazole moiety, showed desirable neuroprotective activity in a rat transient middle cerebral artery occlusion model. Furthermore, compound 4b displayed a high binding affinity for neurotoxin receptor site 2 of the Na(+) channels, which suggests that 4b would act as a use-dependent Na(+) channel blocker in sustained depolarization during ischemic stroke.
Assuntos
2-Propanol/química , Microssomos Hepáticos/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Bloqueadores dos Canais de Sódio/síntese química , Bloqueadores dos Canais de Sódio/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , 2-Propanol/farmacocinética , 2-Propanol/farmacologia , 2-Propanol/uso terapêutico , Animais , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , Microssomos Hepáticos/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Wistar , Bloqueadores dos Canais de Sódio/farmacocinética , Bloqueadores dos Canais de Sódio/uso terapêuticoRESUMO
In the screening for muscarinic M3 receptor binding inhibitors from microbial secondary metabolites, the extract of Nocardia sp. TP-A0674 was found to be highly active. Bioassay-guided fractionation of it led to the isolation of six new siderophores, nocardimicins A (1), B (2), C (3), D (4), E (5), and F (6), as active principles. Their chemical structures were determined by spectroscopic and degradation analysis. Of these congeners, nocardimicin B (2) inhibited the binding of tritium-labeled N-methylscopolamine to the muscarinic M3 receptor most potently with a Ki value of 0.13 microM. Compound 2 showed more selective activity to M3 and M4 receptors than other subtypes.
Assuntos
Antagonistas Muscarínicos , Nocardia/química , Receptor Muscarínico M3/antagonistas & inibidores , Sideróforos/isolamento & purificação , Humanos , Japão , Estrutura Molecular , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/isolamento & purificação , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacologia , Sideróforos/química , Sideróforos/farmacologiaRESUMO
A new pyrrolizidine alkaloid, cremastrine (1), was isolated from the bulbs of Cremastra appendiculata. Its configuration was determined by spectroscopic and chemical analyses. Compound 1 inhibited the binding of tritium-labeled N-methylscopolamine to the muscarinic M3 receptor with a K(i) value of 126 nM.
