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 K i =8±1 nM (vs [ 3 H]thienylcyclidine, [ 3 H]TCP) as a mixture of enantiomers. Resolution and further testing indicate that (-)-2, K i =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 (IC 50 =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