| Budget Amount *help |
¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2006: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
|
|---|
| Research Abstract |
Glutamate is a major excitatory neurotransmitter in mammalian central nervous systems and is linked to higher brain functions such as memory and learning. Glutamate is concentrated into synaptic vesicles through Vesicular Glutamate Transporters (VGLUTs) and is stocked in vesicles in nerve endings. As known inhibitors also show affinity for glutamate receptors and synaptic glutamate transporters (EAATs), selective inhibitors for VGLUTs have been required. It would be important that inhibitors permeate plasma membrane to inhibit VGLUTs inside neurons. In order to improve selectivity for VGLUTs, potency, and cell membrane permeability, we synthesized novel trans-ACPD derivatives. First, we synthesized methyl analogs to examine the position and stereochemistry of a substituent. Among them, 5R-methyl analog showed inhibition of glutamate uptake into vesicles. Thus, we tried to introduce a hydroxyl analog and ether analogs to examine the effects of a substituent. Similar to the synthetic scheme of methyl analogs, alkylidenecarbene prepared from the corresponding ketone was applied for the benzyloxy analog. However, benzyl position reacted to give an ether ring instead of the five membered-ring cyclization. We examine other protective groups on the hydroxyl group to overcome this problem. Furthermore, to improve the cell membrane permeability, γ-carboxyl group was converted into methyl ester (ACPD-OMe). ACPD-OMe didn't inhibit the transport of glutamate into the isolated vesicles, while it decreased the glutamate transport using synaptosomes. On the other hand, trans-ACPD didn't affect the glutamate transport when synaptosomes were used. ACPD-OMe would be converted to trans-ACPD by enzyme after membrane permeation and, then, inhibit VGLUTs. These results demonstrate that the modification of carboxylic acid is useful for the improvement of cell membrane permeability and development of novel type of VGLUT inhibitors.
|
