Bimrgonic & Medicinal Chemistry Letters. Vo1.3. No.1, pi. 85-90. 1993 Printed in Great Britain 0960-894x193 $5.00 + .oO 0 1993 Pagamon Press Ltd INTERACTION OF RIGID FOLYAMINE ANALOGURS WITH THE NMDA RECEPTOR COMPLEX FROM RAT BRAIN Ian J. Reynolds*, Kristi D. Rothermund and Sunita Rrjdev Department of Pharmacology, University of Pittsburgh, El354 Biomedical Science Tower, Pittsburgh PA 15261, U.S.A. Abstract: We investigated four compounds that may be considered rigid analogues of hiamine polyamines that bind to the NMDA receptor. Ethidium, propidium, safranine T and phenosafranine all inhibited [‘III dizocilpine binding to the NMDA receptor (IC, values 2-5pM). However, only propidium appeared to interact with the polyamine site. Activity of the N-methyl-D-aspartate (NMDA) preferring subtype of glutamate receptor is controlled by a host of endogenous substances that includes glycine, Mg2+, Zn2+, H+ and sulfhydryl redox reagents14. Any of these agents may alter the activity of the NMDA receptor in viva, although in most cases their actual role remains unknown. The polyamines spermine and spermidine were recently added to the list of putative endogenous NMDA receptor modulators5, based on their ability to allosterically increase [‘HI dizocilpine binding to the receptor complex. Subsequent studies have revealed that polyamines probably bind to at least two different sites on the recepto$. A high affinity site is responsible for increasing [‘HI dizocilpine binding, and the action of polyamines at this site can be competitively antagonized by d&ionic compounds like arcaine (l,4-bisguanidinobutane)7 and diaminodecane @AlO)*. The lower affinity site mediates polyamine inhibition of PH] dizocilpine binding, and is relatively insensitive to arcaine and DAlO. The contribution of the polyamine site to the function of the NIvfDA receptor is poorly understood. However polyamine binding to the low affinity site may increase the affinity of glycineg*rO, thereby promoting activation of the receptor”, while antagonists at the high affinity site may reverse the effects of drugs like dizocilpine and phencyclidine6. 85