Synthesis, chiral resolution, and enantiopharmacology of a potent 2,3-benzodiazepine derivative as noncompetitive AMPA receptor antagonist.
This paper describes the synthesis of racemic 3,5-dihydro-5-methyl-7,8-methylenedioxy-4H-2,3-benzodiazepin-4-one (+/-)-5, attempted stereoselective synthesis of its enantiomers, chiral HPLC resolution of the racemate, and assignment of the absolute configuration. Enantiomer (5S)-(-)-5 is provided with an in vivo anticonvulsant activity 8 times higher than its enantiomer (5R)-(+)-5. This result is confirmed in the in vitro test by the ability to inhibit the kainate-induced increase of the [Ca(2+)](i) in a primary culture of rat cerebellar granule cells which express alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Binding affinity of compound (+/-)-5 at the AMPA and N-methyl-d-aspartic acid (NMDA) receptors was also evaluated.
Zappalà
Maria
M
Dipartimento Farmaco-Chimico, Università di Messina, 98168 Messina, Italy.
Postorino
Giovanna
G
Micale
Nicola
N
Caccamese
Salvatore
S
Parrinello
Nunziatina
N
Grazioso
Giovanni
G
Roda
Gabriella
G
Menniti
Frank S
FS
De Sarro
Giovambattista
G
Grasso
Silvana
S
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D008968:Molecular Conformation; D016548:Prosencephalon / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy; D013237:Stereoisomerism
C508795:3,5-dihydro-5-methyl-7,8-methylenedioxy-4H-2,3-benzodiazepin-4-one; D000927:Anticonvulsants; D001570:Benzodiazepinones; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D001569:Benzodiazepines; D007608:Kainic Acid; D002118:Calcium