Molecular Features Associated with Polyamine Modulation of NMDA Receptors

Abstract

The effect of 1,3-diamines on basal and spermine-stimulated [3H]MK-801 binding was investigated. Systematic variations in the molecular parameters revealed that, in general, lipophilic 1,3-diamines inhibited and hydrophilic 1,3-diamines enhanced [3H]MK-801 binding in the nominal absence of glutamate and glycine. Furthermore, 1,3-diamines which were highly monoprotonated at physiologic pH were more effective in modulating basal binding (at 100 microM 1,3-diamine) than analogues which were mostly diprotonated or unprotonated. Finally, the internuclear distance between the amino nitrogens and the extent of modulation of basal [3H]MK-801 binding were correlated. Similar, but more modest, effects were seen for spermine-enhanced [3H]MK-801 binding. These results are consistent with the existence of two polyamine binding sites associated with the NMDA receptor complex. One of the sites appears to preferentially recognize lipophilic substances while the other favors hydrophilic materials. Both sites appear to recognize polyamines with at least one charged (protonated) amino group and one uncharged amino group. The distance between amino groups is a determining factor as well.

Protonation sites on unsymmetrical 1,3-diamines: a nuclear magnetic resonance study of 3-aminotropanes

“…The near identity of the experimentally determined pK 1 values of 2 and 3 (10.90 and 10.89) 4 indicate the similarity of the tertiary amino groups in the two isomers. The significant difference between the pK 2 values of 2 and 3 (7.56 and 8.02, 4 respectively) might be related to the greater effect of protonation of the tertiary amino group in 2 than in 3, or to greater steric hindrance of the axial amino group in the˛-isomer 2 relative to the equatorial amino group in theˇ-isomer 3.…”

“…4 The pH values at which the concentration of the monoprotonated species (BH) is highest were calculated from the previously determined 4 pK values. The concentrations of the diprotonated, monoprotonated (BH) and unprotonated (B) species as a function of pH are shown in Table 1.…”

“…the hydrogen at C-3, the 1,5-bridgehead hydrogens and the N-CH 3 group hydrogens, are shifted upfield by about 1 ppm in basic relative to acidic medium [see (2-14) in Table 1]. At pH 9.1 and 9.2 for 2 and 3, respectively, where, based on the experimental pK values, 4 the˛-isomer 2 is 95.7% monoprotonated and theˇ-isomer 3 is 92.1% monoprotonated (Table 1), the H-3 resonances are shifted by 0.4 and 0.45 ppm [see (2-9) in Table 1], representing 40-50% of the maximum shift, (2-14) in Table 1, whereas the H-1, H-5 and N-CH 3 resonances are shifted by only 0.08-0.2 ppm. These observations suggest deprotonation of the primary amino group at pH 9 and indicate that the tertiary amino group is more basic than the primary amino group in both isomers.…”

“…The significant difference between the pK 2 values of 2 and 3 (7.56 and 8.02, 4 respectively) might be related to the greater effect of protonation of the tertiary amino group in 2 than in 3, or to greater steric hindrance of the axial amino group in the˛-isomer 2 relative to the equatorial amino group in theˇ-isomer 3. We had found, 4 in a series of aliphatic 1,3-diamines, the effect of protonation of the more basic amino group on the pK of the second amino group to be a function of the distance between the amino groups. If the conformations of the piperidine moiety of the 3-aminotropanes 2 and 3 are chair-like, the two amino groups in both are gauche and essentially equidistant from each other.…”

Kinetic Template‐Guided Tethering of Fragments

“…Subsequent analysis by ESI MS indicated that the TS-54 adduct was still intact. As this fragment contains a basic amine, with a pKa value of approximately the same value as for negative control 68, [178,179] it was considered that it may act via a similar base-catalysed intramolecular thiol deprotonation mechanism, Figure 77. Whilst this could not be ruled out, this ligand did not show a tethering dependence on pH between 8.1 -7.2 as was observed for negative control 68.…”