Discovery of 6,11-ethano-12,12-diaryl-6,11-dihydrobenzo[b]quinolizinium cations, a novel class of N-methyl-D-aspartate antagonists.
6,11-Ethano-12,12-diaryl-6,11-dihydrobenzo[b]quinolizinium cations 8, a novel class of N-methyl-D-aspartate (NMDA) antagonists acting at the phencyclidine site, have been identified. Structure-activity relationship studies around the lead compound 8a led to the identification of 12g (WIN 67870-2), one of the most potent compounds in this series. Compound 12g has a Ki = 1.8 +/- 0.2 nM vs [3H]TCP binding, has 700-fold selectivity for binding to the open state of the NMDA receptor-ionophore, and was devoid of MK-801- and PCP-like behavioral effects in rats. Compound 12g was neuroprotective in cultured mouse cortical neurons and exhibited antiischemic activity in a rat middle cerebral artery occlusion/reperfusion model of focal ischemia.
Department of Medicinal Chemistry, Sterling Winthrop Pharmaceuticals Research Division, Collegeville, Pennsylvania 19426-0900.
C
C
Subramanyam
J P
JP
Mallamo
J A
JA
Dority
W G
WG
Earley
V
V
Kumar
L D
LD
Aimone
B
B
Ault
M S
MS
Miller
D A
DA
Luttinger
D L
DL
DeHaven-Hudkins
D000818:Animals; D001665:Binding Sites; D002545:Brain Ischemia / Q000188:drug therapy; D002412:Cations; D004594:Electrophysiology; D010622:Phencyclidine / Q000378:metabolism; D011806:Quinolinium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D011807:Quinolizines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D002412:Cations; D011806:Quinolinium Compounds; D011807:Quinolizines; D016194:Receptors, N-Methyl-D-Aspartate; D010622:Phencyclidine