ABSTRACT
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.
ABSTRACT
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.
Subject(s)
2-Propanol/chemistry , Microsomes, Liver/drug effects , Neuroprotective Agents/pharmacology , Sodium Channel Blockers/chemical synthesis , Sodium Channel Blockers/pharmacology , Stroke/drug therapy , 2-Propanol/pharmacokinetics , 2-Propanol/pharmacology , 2-Propanol/therapeutic use , Animals , Disease Models, Animal , Infarction, Middle Cerebral Artery/drug therapy , Male , Microsomes, Liver/metabolism , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/pharmacokinetics , Neuroprotective Agents/therapeutic use , Rats , Rats, Wistar , Sodium Channel Blockers/pharmacokinetics , Sodium Channel Blockers/therapeutic useABSTRACT
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.
Subject(s)
Muscarinic Antagonists , Nocardia/chemistry , Receptor, Muscarinic M3/antagonists & inhibitors , Siderophores/isolation & purification , Humans , Japan , Molecular Structure , Muscarinic Antagonists/chemistry , Muscarinic Antagonists/isolation & purification , Muscarinic Antagonists/pharmacokinetics , Muscarinic Antagonists/pharmacology , Siderophores/chemistry , Siderophores/pharmacologyABSTRACT
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.
