ESR Study on the Antioxidant Activity of TAK-218 in Biological Model Membranes

• Published in: Chemical & pharmaceutical bulletin Vol. 48; no. 6; pp. 784 - 792
• Main Authors: MURAKAMI, Morio, FUKATSU, Kohji, OHKAWA, Shigenori, KASAHARA, Fumiko, SUGAWARA, Tohru
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 01.06.2000; Maruzen; Japan Science and Technology Agency
• Subjects: antioxidant activity; Antioxidants - chemistry; Antioxidants - pharmacology; Benzofurans - chemistry; Benzofurans - pharmacology; Biological and medical sciences; biological model membrane; Electron Spin Resonance Spectroscopy; ESR; Free Radical Scavengers - chemistry; Free Radical Scavengers - pharmacology; General and cellular metabolism. Vitamins; Lipid Peroxidation - drug effects; Liposomes; Medical sciences; Membrane Fluidity; Membranes, Artificial; Pharmacology. Drug treatments; spin-label technique; TAK-218; α-tocopherol; DPPH; EPR spectrometry; Liposome; Spin label technique; Lipids; Biomembrane; Antioxidant; Oxygen heterocycle; In vitro; Radical scavenger; Biological activity; Hyperoxides; Piperidine derivatives; Bicyclic compound; Hydroxyl radicals; Aromatic compound; Inhibition; Primary amine; Peroxidation
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.48.784

TAK-218 has a 2, 3-dihydrobenzofuran-5-amine (coumaran) structure which resembles α-tocopherol, and is a promising candidate as an agent for central nervous system (CNS) trauma and ischemia. The radical scavenging activity of TAK-218 was studied using electron spin resonance (ESR) spectroscopy.TAK-218 exhibited a more potent scavenging activity towards the hydroxyl radical than did the well-known hydroxyl radical scavengers, mannitol and dimethylsulfoxide. Towards the superoxide radical, TAK-218 showed equal potency to glutathione. TAK-218 reacted rapidly with stable radicals, such as galvinoxyl and 2, 2-diphenyl-1-picrylhydrazyl hydrate (DPPH), and gave the quinone as a two-electron oxidized product in analogy with α-to-copherol.To exhibit an excellent antioxidative activity in living systems, the compounds should not only have the intrinsic radical scavenging activity but also good distribution in the biological lipid-bilaver membrane. To examine the antioxidant activity of TAK-218, the inhibition of lipid peroxidation by α-tocopherol and TAK-218 in liposomal membranes was studied usign an ESR spin-label technique.Both α-tocopherol and TAK-218 completely inhibited lipid peroxidation by radicals generated in an aqueous layer using a water-soluble radical initiator, 2, 2'-azobis-(2-amidinopropane) hydrochloride (AAPH). At a high incubation temperature (45°C), α-tocopherol scavenged radicals more effectively than TAK-218 on the surface of the membrane, while TAK-218 scavenged radicals more effectively in the interior of the membrane. The difference between TAK-218 and α-tocopherol for radical scavenging in the membrane system derives from the different distribution pattern of these compounds. TAK-218 can penetrate the membrane freely and can scavenge the radical in the membrane interior.Furthermore, TAK-218 was shown to inhibit lipid peroxidation initiated by a lipid soluble radical initiator, 2, 2'-azobis-(2, 4-dimethylvaleronitrile)(AMVN), in a membrane more effectively than α-tocopherol.