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

• Published in: Neuroscience letters Vol. 203; no. 1; pp. 25 - 28
• Main Authors: Berger, Michael L., Khomutov, Alex R., Rebernik, Patrick
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 12-01-1996; Elsevier
• Subjects: [ 3H]MK-801; Aminooxy; Animals; Binding, Competitive; Biological and medical sciences; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Dizocilpine Maleate - pharmacology; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; Hippocampus - drug effects; Male; N-Methyl- d-aspartate receptor complex; Partial agonist; Polyamines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate - drug effects; Spermidine; Spermidine - analogs & derivatives; Spermidine - pharmacology; Vertebrates: nervous system and sense organs; Aminooxy; Partial agonist; [ 3H]MK-801; N-Methyl- d-aspartate receptor complex; Polyamines; Spermidine; Agonist; Polyamine; Rat; Rodentia; Central nervous system; Glutamate receptor; Binding site; Vertebrata; Mammalia; Analog; Antagonist; NMDA receptor; Hippocampus; Brain (vertebrata)
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/0304-3940(95)12255-9

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.