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.
Department of Medicinal Chemistry, University of Florida, J. Hillis Miller Health Center, Gainesville 32610.
R J
RJ
Bergeron
W R
WR
Weimar
Q
Q
Wu
J K
JK
Austin
J S
JS
McManis
D000818:Animals; D001665:Binding Sites; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D011073:Polyamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*
D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate