Identification, synthesis, and characterization of a unique class of N-methyl-D-aspartate antagonists. The 6,11-ethanobenzo[b]quinolizinium cation.
A series of novel N-methyl-D-aspartate antagonists acting at the phencyclidine site has been identified. Compound 2 has a Ki = 8 +/- 1 nM (vs [3H]thienylcyclidine, [3H]TCP) as a mixture of enantiomers. Resolution and further testing indicate that (-)-2, Ki = 4 +/- 0.7 nM, is a potent and selective TCP site ligand with neuroprotective activity in cultured neurons in the presence of excitotoxic concentrations of NMDA (IC50 = 26 nM). Compound (-)-2 is > 1000-fold selective for the TCP site vs a panel of receptor types including opiate, adrenergic, serotonergic, dopamine, adenosine, dihydropyridine, and benzodiazepine and displays increased selectivity for the activated (open) NMDA receptor-ion channel complex vs PCP and MK801 as measured by patch recordings in cultured, voltage-clamped neurons. Highly enhanced "open-channel" selectivity leads to tentative classification of these ligands as uncompetitive vs NMDA. Ligands with these characteristics may enable deconvolution of the pharmacologic effects associated with typical noncompetitive NMDA antagonists. We report here on the identification, synthesis, and activity of compounds of this structural class.
Mallamo
J P
JP
Department of Medicinal Chemistry, Sterling Winthrop Pharmaceuticals Research Division, Collegeville, Pennsylvania 19426-0900.
Earley
W G
WG
Kumar
V
V
Subramanyam
C
C
Dority
J A
JA
Miller
M S
MS
DeHaven-Hudkins
D L
DL
Ault
B
B
Herrmann
J L
JL
Dung
J S
JS
D000818:Animals; D001665:Binding Sites; D007473:Ion Channels / Q000187:drug effects; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D007473:Ion Channels; D018696:Neuroprotective Agents; D016202:N-Methylaspartate; C012058:tenocyclidine; D010622:Phencyclidine