Novel benzo[b]quinolizinium cations as uncompetitive N-methyl-D-aspartic acid (NMDA) antagonists: the relationship between log D and agonist independent (closed) NMDA channel block.
A series of permanently charged benzo[b]quinolizinium cations having lower lipophilicity than MK-801 or phencyclidine (PCP) were synthesized. Data relating agonist independent block of N-methyl-D-aspartic acid (NMDA) ion channels to log D are described. Closed channel access is predicted to result in a more noncompetitive profile of antagonism compared to selective open channel blockers, which are uncompetitive inhibitors. Reduced closed channel block may underlie the absence of PCP or MK-801-like behavioral side effects observed for benzo[b]-quinolizinium cations.
Earley
W G
WG
Department of Medicinal Chemistry, Sanofi Research Division, Sanofi Winthrop Inc. Collegeville, Pennsylvania 19426-0900, USA.
Kumar
V
V
Mallamo
J P
JP
Subramanyam
C
C
Dority
J A
JA
Miller
M S
MS
DeHaven-Hudkins
D L
DL
Aimone
L D
LD
Kelly
M D
MD
Ault
B
B
D000818:Animals; D001665:Binding Sites; D002412:Cations; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000031:analogs & derivatives / Q000737:chemistry; D005260:Female; D066298:In Vitro Techniques; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009865:Oocytes / Q000166:cytology; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000737:chemistry; D011807:Quinolizines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D002412:Cations; D011807:Quinolizines; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D010622:Phencyclidine