An antagonist/partial agonist at the polyamine recognition site of the N-methyl-D-aspartate receptor that alters the properties of the glutamate recognition site

K Williams, LM Pullan, C Romano, RJ Powel, AI Salama and PB Molinoff

Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia.

The effects of N-(3-aminopropyl)-1,10-diaminodecane (APDA10) on the N- methyl-D-aspartate (NMDA) receptor/ion channel complex were investigated. In the presence of 100 microM glutamate and 100 microM glycine, APDA10 had biphasic effects on the binding of [3H](+)-5-methyl- 10,11-dihydro-5H-dibenzo[a,d]cyclohepten5,10-imin e (MK-801) to NMDA receptors on well washed synaptic plasma membranes. The maximal stimulation of binding by APDA10 was less than that seen with spermine. In the presence of glutamate and glycine, APDA10 attenuated the stimulatory effect of spermine and the inhibitory effect of 1,10- diaminodecane. In the nominal absence of glutamate and glycine, APDA10 had no effect on the binding of [3H]MK-801, but antagonized the stimulatory effect of spermine on the binding of [3H] MK-801. These data suggest that APDA10 acts as a mixed antagonist/partial agonist at the polyamine recognition site, and that the partial agonist properties of APDA10 are dependent on the activation state of the receptor complex. An increase in the potency of the glutamate site antagonists D- 2-amino-5-phosphonovaleric acid and 3-(2-carboxypiperazin-4-yl)-propyl- 1-phosphonic acid for inhibiting the binding of [3H]MK-801 was seen in the presence of APDA10. APDA10 also increased the affinity of binding of [3H]3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid to the NMDA receptor complex but had no effect on the binding of [3H]glycine. These data suggest that the polyamine APDA10 may alter the properties of the glutamate recognition site on the NMDA receptor complex.

Volume 262, Issue 2, pp. 539-544, 08/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics