(−)-Arctigenin and a series of new analogues have been synthesised and then tested for their potential as AMPA and kainate receptor antagonists of human homomeric GluA1 and GluK2 receptors expressed in HEK293 cells using a Ca2+ influx assay. In general, these compounds showed antagonist activity at both receptors with greater activity evident at AMPARs. Schild analysis indicates that a spirocyclic analogue 6c acts as a non-competitive antagonist. Molecular docking studies in which 6c was docked into the X-ray crystal structure of the GluA2 tetramer suggest that (−)-arctigenin and its analogues bind in the transmembrane domain in a similar manner to the known AMPA receptor non-competitive antagonists GYKI53655 and the antiepileptic drug perampanel. The arctigenin derivatives described herein may serve as novel leads for the development of drugs for the treatment of epilepsy.
|Number of pages||9|
|Journal||Organic and Biomolecular Chemistry|
|Early online date||13 Oct 2021|
|Publication status||Published - 14 Nov 2021|
FunderFunding Information: We are grateful to the Bristol Chemical Synthesis Doctoral Training Centre funded by EPSRC (EP/G036764/1) for a studentship (L-MR) and ERC grant (HippoKAR) for financial support for RJT. EM and DEJ were supported by the Biotechnology and Biological Sciences Research Council (Grant BB/J015938/1) and GLC by CIHR (Canadian Institute of Health Research) award FDN154276. SM was a Shah Abdul Latif University-funded PhD student.
ASJC Scopus subject areas
- Physical and Theoretical Chemistry
- Organic Chemistry