ABSTRACT
We have synthesized a series of new ß-carboline-tripeptide conjugates, and examined their anti-inflammatory properties in a mouse model of xylene-induced ear edema. The analgesic capacity of these compounds was further evaluated in a rodent tail flick assay. Our results indicate that ß-carboline conjugate 4a manifests potent anti-inflammatory and analgesic activity while exerting a protective effect against mesenteric ischemia/reperfusion (I/R) injury in the rat.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Carbolines/chemistry , Mesenteric Arteries/drug effects , Oligopeptides/pharmacology , Reperfusion Injury/drug therapy , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Edema/chemically induced , Edema/prevention & control , Male , Mesenteric Arteries/pathology , Mice , Mice, Inbred ICR , Models, Molecular , Molecular Dynamics Simulation , Molecular Structure , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Rats , Rats, Wistar , Reperfusion Injury/pathology , Stereoisomerism , Xylenes/antagonists & inhibitorsABSTRACT
We describe a novel class of ß-carboline alkaloid-peptide conjugates that possess both free radical scavenging and thrombolytic activity. These conjugates demonstrate therapeutic efficacy in a rat arterial thrombosis assay, as well as free radical scavenging capacity as evaluated in a PC12 cell survival assay. Our results indicate that ß-carboline alkaloid-peptide conjugate 26a exerts a significant protective effect against local and remote organ injury induced by limb I/R injury in the rat.
Subject(s)
Alkaloids/pharmacology , Carbolines/pharmacology , Extremities/blood supply , Ischemia/drug therapy , Peptides/pharmacology , Reperfusion Injury/drug therapy , Acute Disease , Alkaloids/chemical synthesis , Alkaloids/chemistry , Animals , Carbolines/chemical synthesis , Carbolines/chemistry , Cell Survival/drug effects , Extremities/pathology , Free Radical Scavengers/metabolism , Ischemia/pathology , Molecular Dynamics Simulation , Molecular Structure , PC12 Cells , Peptides/chemical synthesis , Peptides/chemistry , Rats , Reperfusion Injury/pathology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
To develop more potent therapeutic agents with therapeutic efficacy for ischemia/reperfusion (I/R) injury, we linked an antiinflammatory moiety (1,3-dioxane derivative) to the key pharmacophoric moiety of melatonin. We hypothesized that the resulting new indole derivatives might induce a synergistic protection against oxidative damage associated with I/R injury. Our results indicate that one of these indole derivatives (7) manifests potent antiinflammatory antioxidant effects and exerts a protective effect against skeletal muscle injury and associated lung injury following limb I/R in rats.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Antioxidants/chemical synthesis , Indoles/chemical synthesis , Reperfusion Injury/drug therapy , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antioxidants/chemistry , Antioxidants/pharmacology , Capillary Permeability , Free Radical Scavengers/chemical synthesis , Free Radical Scavengers/chemistry , Free Radical Scavengers/pharmacology , Hindlimb/blood supply , Indoles/chemistry , Indoles/pharmacology , Inflammation/drug therapy , Lipid Peroxidation/drug effects , Lung Injury/drug therapy , Lung Injury/metabolism , Lung Injury/pathology , Mice , Muscle, Skeletal/blood supply , Muscle, Skeletal/drug effects , Muscle, Skeletal/pathology , PC12 Cells , Rats , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , Structure-Activity RelationshipABSTRACT
Renal ischemia/reperfusion is a common cause of acute renal failure. Glycine is an effective anti-inflammatory, cytoprotective agent and is reported to have a beneficial effect against ischemia/reperfusion injury in various organs. Previous research notes that free radicals and inflammatory leukocytes both play important roles in the pathogenesis of renal ischemia/reperfusion injury. To develop new therapeutic agents against renal ischemia/reperfusion injury, we sought to link an antioxidant moiety (nitronyl nitroxide) to glycine in the hope that the resulting glycine-nitronyl nitroxide conjugate (GNN) would provide a synergetic protection against renal ischemia/reperfusion injury. In this manuscript, we report the synthesis and biological evaluation of the GNN conjugate. The biological activity of the GNN conjugate was evaluated in an in vivo rat model of renal ischemia/reperfusion induced injury and oxidative change. Since the GNN conjugate markedly reduced elevated levels of tissue lipid peroxidation and attenuated renal dysfunction in rats subjected to renal ischemia/reperfusion, it might be possible to develop the GNN conjugate into a potential therapeutic agent against renal ischemia/reperfusion injury.
