Polyamines and the NMDA receptor: Modifying intrinsic activities with aromatic substituents

The inhibiting effects of 34 spermidine and spermine derivatives on the binding of [ 3H]MK-801 to NMDA receptors on rat brain membranes were investigated. Several compounds, including 1c, appeared to inhibit radioligand binding via the polyamine regulatory site, whereas others, including 2c, more likely acted directly at the channel. Thirty-four spermidine (SPD) and spermine (SPM) derivatives with aromatic substituents were synthesized and tested as inhibitors of specific binding of the NMDA channel blocker [ 3H]MK-801 to membranes prepared from rat hippocampus and cerebral cortex. SPD and SPM derivatives with aromatic substituents at the primary amino groups were the most potent inhibitors (IC 50 3.9–4.7 μM). These compounds most likely act directly at the NMDA ion channel, since 30 μM SPM had no pronounced influence on their inhibiting activities. SPD derivatives with aromatic substituents at the secondary amino group were either inactive or highly SPM-sensitive inhibitors (IC 50 10–82 μM), depending on the size of the substituent. Our results support the hypothesis that an aromatic interaction site near the center of polyamine derivatives contributes to polyamine inverse agonism.