|
Summary of Research Projects (Supports in 2003
Fiscal Year)
| Subjects |
Development of Subtype-Selective Ligands for Glutamate Receptors |
| Representative researcher |
Tohoku University Makoto SASAKI |
| Joint researcher |
Tohoku University Masato OIKAWA |
| Kitasato University Ryuichi SAKAI |
| Dysiherbaine (1) is a
marine sponge-derived excitatory amino acid with potent convulsant
activity. This novel amino acid activates neuronal non-N-methyl-D-aspartate
(non-NMDA) type glutamate receptors (GluR), namely, AMPA
and kainic acid (KA) receptors, with considerable preference
over KA receptors. Moreover, characterization of DH actions
on recombinant GluRs revealed that the selective binding
to the GluR5 and GluR6 subunits was of high affinity. Because
of these intriguing pharmacological properties to KA receptors,
as well as its potent epileptogenic action, DH and its designed
analogues are anticipated to serve as useful tools for investigating
GluR structure and function in the central nervous system.
In order to reveal detailed structure-activity relationship
profiles of dysiherbaines, we have developed a concise and
efficient synthetic route to dysiherbaine analogue 4. The
synthesis features a stereoselective C-glycosidation to set
the C6 stereocenter and epoxide opening/ring closure
to form tetrahydrofuran ring. We also characterized the pharmacological
activity of simplified model compound 3, which lacks the
C8 and C9 functional groups of dysiherbaine.
Radioligand binding assays and electrophysiological studies
revealed compound 3 to be a selective antagonist to GluR5 KA receptor. |
|
Japanese 
returns
to the list