Aminooxy-analogues of spermidine: new partial agonists and antagonists at the polyamine site of the rat hippocampal NMDA receptor complex

Abstract

The amino-1-oxy- and amino-8-oxy-analogues of spermidine (1-O-SPD and 8-O-SPD) were tested in vitro with rat hippocampal membranes as potential modulators of the N-methyl- d-aspartate (NMDA) receptor complex via the polyamine regulatory site. In the presence of 1 μM glutamate and glycine, the binding of the NMDA channel ligand [ 3H]MK-801 was stimulated by 8-O-SPD (EC 50 = 50 μM); 1-O-SPD was without significant influence at concentrations up to 1 mM. Addition of 2 and 4 μM of the polyamine agonist spermine eliminated the stimulatory property of 8-O-SPD, whereas 1-O-SPD was inhibitory under these conditions (IC 50 = 274 and 481 μM, respectively). At higher concentrations of spermine, both compounds were inhibitory. Inhibition of [ 3H]MK-801 binding by the inverse polyamine agonists 1,10-diaminodecane, 1,12-diaminododecane, and arcaine was attenuated by 1 mM 1-O-SPD. The data are compatible with the notion that 8-O-SPD is a partial polyamine agonist and that 1-O-SPD is an antagonist without intrinsic activity.