Structure-activity relationships of competitive NMDA receptor antagonists.
The interaction of structurally constrained competitive NMDA receptor antagonists, (+/-)-cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755), (2-amino-4,5-(1,2-cyclohexyl))-7-phosphonoheptanoic acid (NPC 12626), (+/-)-6-phosphonomethyl-de-cahydroisoquinoline-3-carboxylic acid (LY 274614), (S)-alpha-amino-5-phosphonomethyl[1,1'-biphenyl]-3-propanoic acid (SDZ EAB-515) and (S)-alpha-amino-5-phosphonomethyl[1,1':4',1"-terphenyl]-3-propa noi c acid (SDZ 215-439), with their receptor was assessed using radioligand binding, protection against neurotoxicity in cortical neuronal cultures and computerised molecular modelling. All compounds inhibited the specific binding of [3H]CGS 19755 and/or [3H]CGP 39653 (inhibition constants 40-2000 nM), and protected neuronal cultures from NMDA-mediated injury (IC50 values 1.3-5.6 microM). Quantitative conformational analyses indicated that the molecules fitted well to a NMDA receptor model. Our results draw attention to a deep hydrophobic pocket, defined by the bi- and terphenyl containing antagonists (SDZ EAB-515, SDZ 215-439), which may influence potency and selectivity.
Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
N S
NS
Cheung
D
D
O'Callaghan
M C
MC
Ryan
R
R
Dutton
M G
MG
Wong
P M
PM
Beart
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism*; D007546:Isoquinolines / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D009474:Neurons / Q000378:metabolism; D010875:Pipecolic Acids / Q000378:metabolism; D011422:Propionates / Q000378:metabolism; D011869:Radioligand Assay; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism* / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000596:Amino Acids; D001713:Biphenyl Compounds; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D010875:Pipecolic Acids; D011422:Propionates; D016194:Receptors, N-Methyl-D-Aspartate; C060212:NPC 12626; C077642:2-amino-5-phosphonomethyl(1,1'-biphenyl)-3-propanoic acid; C070935:LY 274614; C053672:selfotel