Enantiomerically pure tetrahydroquinoline derivatives as in vivo potent antagonists of the glycine binding site associated to the NMDA receptor.
To identify neuroprotective agents after stroke, new substituted tetrahydroquinoline derivatives were designed as antagonists of the glycine binding site associated to the NMDA receptor, satisfying the key pharmacophoric requirements. In particular, the racemate 3c exhibited outstanding in vivo activity in the MCAo model in rats, when given iv both pre- and post-ischemia. Pure enantiomers 3c-(+) and 3c-(-) have been prepared following an original synthetic route. Despite the significant difference of activity observed in vitro, they shown similar neuroprotective profile in the MCAo model in rats.
Di Fabio
Romano
R
Medicines Research Centre, GlaxoSmithKline S.p.A, Via Fleming 4, 37135 Verona, Italy. rdf26781@gsk.com
Tranquillini
Elvira
E
Bertani
Barbara
B
Alvaro
Giuseppe
G
Micheli
Fabrizio
F
Sabbatini
Fabio
F
Pizzi
Maria Domenica
MD
Pentassuglia
Giorgio
G
Pasquarello
Alessandra
A
Messeri
Tommaso
T
Donati
Daniele
D
Ratti
Emiliangelo
E
Arban
Roberto
R
Dal Forno
Giovanna
G
Reggiani
Angelo
A
Barnaby
Robert J
RJ
D000818:Animals; D001665:Binding Sites; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D020768:Middle Cerebral Artery; D008968:Molecular Conformation; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
D018696:Neuroprotective Agents; D011804:Quinolines; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate