Separation of alpha 1 adrenergic and N-methyl-D-aspartate antagonist activity in a series of ifenprodil compounds.

Ifenprodil (1) represents a new class of N-methyl-D-aspartate (NMDA) antagonist. This drug also possesses potent activity at several other brain receptors (most notably alpha 1 adrenergic receptors). We have prepared the enantiomers and diastereomers of ifenprodil along with a series of partial structures in order to explore the basic structure activity relations within this class of compounds. From this study, it is clear that alpha 1 adrenergic and NMDA receptor activities may be separated by selection of the threo relative stereochemistry. Examination of the optical isomers of threo-ifenprodil (2) reveals that no further improvement in receptor selectivity is gained from either antipode. Individual removal of most of the structural fragments from the ifenprodil molecule generally results in less active compounds although fluorinated derivative 9 with threo relative stereochemistry is somewhat more potent and substantially more selective for the NMDA receptor. Finally a minimum structure for activity in this series (14) has been identified. This stripped-down version of ifenprodil possesses nearly equivalent affinity for the NMDA receptor with no selectivity over alpha 1 adrenergic receptors.