Impact of polyamine analogues 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 microM L-glutamate and 100 microM glycine. At low micromolar polyamine concentrations, these analogs enhance binding of [3H]-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-im ine ([3H]MK-801) similar to spermine (SPM). At higher concentrations (e.g., > or = 10 microM), the analogs are antagonists of [3H]MK-801 binding. The most potent analog, N1,N14-bis(1-adamantyl)homospermine, is almost totally devoid of agonist activity and is a potent antagonist at concentrations > or = 5 microM. 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.