Synthesis of thieno[2,3-d]oxazines and thieno[2,3-d]thiazines as subtype specific kainate receptor antagonists.
For the development of new antiepileptics the kainate receptors GluR6 and GluR5 are important targets. Based on the anticonvulsant effects of chinazolines and thieno[2,3-d]pyrimidines that are known from the literature, thieno[2,3-d][1.3]oxazines were synthesized and studied for their inhibitory properties at GluR6 and GluR5 receptors. The strongest inhibitor activity was observed with 5-methyl-6-phenyl-thieno[2,3-d][1.3]oxazines with C1 or C3-substituents in position 2 (3b-f). The 2-trihalide-methyl-substituted compounds 3c and 3d were the most active inhibitors at the GluR5-receptor (IC50=23.4 micromol, 16 microl). The 2-isopropyl-substituted compound 3f displayed the strongest activity at the GluR6-receptor (IC(50)=8.7 micromol). A number of thieno[2,3-d][1.3]thiazines and thieno[2,3-d] pyrimidines that were synthesized from the thieno[2,3][1.3]oxazines did not show any activity.
Briel
D
D
Institute of Pharmacy, Faculty of Biosciences, Pharmacy and Psychology, University of Leipzig, Brüderstrasse 34, 04103 Leipzig, Germany. briel@rz.uni-leipzig.de
Rybak
A
A
Mann
S
S
Kronbach
C
C
Unverferth
K
K
D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000097806:GluK2 Kainate Receptor
D000927:Anticonvulsants; D010078:Oxazines; D011743:Pyrimidines; D018092:Kainic Acid Receptors; D013843:Thiazines; D000097806:GluK2 Kainate Receptor