title: 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.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Sanofi Research Division, Sanofi Winthrop Inc. Collegeville, Pennsylvania 19426-0900, USA.
authors.forename: W G
authors.initials: WG
authors.lastname: Earley
authors.forename: V
authors.initials: V
authors.lastname: Kumar
authors.forename: J P
authors.initials: JP
authors.lastname: Mallamo
authors.forename: C
authors.initials: C
authors.lastname: Subramanyam
authors.forename: J A
authors.initials: JA
authors.lastname: Dority
authors.forename: M S
authors.initials: MS
authors.lastname: Miller
authors.forename: D L
authors.initials: DL
authors.lastname: DeHaven-Hudkins
authors.forename: L D
authors.initials: LD
authors.lastname: Aimone
authors.forename: M D
authors.initials: MD
authors.lastname: Kelly
authors.forename: B
authors.initials: B
authors.lastname: Ault
mesh_terms: 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
chemical_list: D002412:Cations; D011807:Quinolizines; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D010622:Phencyclidine