AMINOOXY-ANALOGS OF SPERMIDINE - NEW PARTIAL AGONISTS AND ANTAGONISTSAT THE POLYAMINE SITE OF THE RAT HIPPOCAMPAL NMDA RECEPTOR COMPLEX

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 potent ial modulators of the N-methyl-D-aspartate (NMDA) receptor complex via the polyamine regulatory site. In the presence of 1 mu M glutamate an d glycine, the binding of the NMDA channel ligand [H-3]MK-801 was stim ulated by 8-O-SPD (EC(50) = 50 mu M); 1-O-SPD was without significant influence at concentrations up to 1 mM. Addition of 2 and 4 mu M of th e polyamine agonist spermine eliminated the stimulatory property of 8- O-SPD, whereas 1-O-SPD was inhibitory under these conditions (IC50 = 2 74 and 481 mu M, respectively). At higher concentrations of spermine, both compounds were inhibitory. Inhibition of [H-3]MK-801 binding by t he 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.