TAK-218 has a 2,3-dihydrobenzofuran-5-amine (
coumaran) structure which resembles
alpha-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
alpha-tocopherol. 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-bilayer membrane. To examine the
antioxidant activity of
TAK-218, the inhibition of lipid peroxidation by
alpha-tocopherol and
TAK-218 in liposomal membranes was studied using an ESR
spin-label technique. Both
alpha-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 degrees C),
alpha-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
alpha-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
alpha-tocopherol.