IMPACT OF POLYAMINE ANALOGS ON THE NMDA RECEPTOR

Several N,N'-terminal dialkylated homologs of the tetraamine spermine exhibit a pronounced biphasic activity at the N-methyl-D-aspartate (NMDA) receptor-channel complex in rat cerebral cortex membranes in the presence of 100 mu M L-glutamate and 100 mu M glycine. At low micromolar polyamine concentrations, these analogs enhance binding of [H-3]-(+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([H-3]MK-801) similar to spermine (SPM). At higher concentrations (e.g., greater than or equal to 10 mu M), the analogs are antagonists of [H-3]MK-801 binding. The most potent analog, N-1,N-14-bis(1-adamantyl)homospermine, is almost totally devoid of agonist activity and is a potent antagonist at concentrations greater than or equal to 5 mu M. Three structural features of the tetraamines studied appear to correlate with potency of inhibition: (1) N-terminally alkylated polyamines > terminal primary amines (e.g., SPM); (2) length of the polyamine backbone, e.g., DMHSPM > DMNSPM; and (3) size of the terminal alkyl groups, i.e., adamantyl > tert-butyl > ethyl > methyl. These findings emphasize the potential. of the tetraamine backbone as a pharmacophore to modulate NMDA receptor-channel function.