Molecular features associated with polyamine modulation of NMDA receptors

Journal of Medicinal Chemistry
A H LewinP Skolnick

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.

References

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Citations

May 10, 2017·Soft Matter·Dongfang LiuHongsheng Lu
Jun 23, 2019·Cellular and Molecular Life Sciences : CMLS·Francisca Sánchez-JiménezJosé Luis Urdiales
Feb 17, 1999·Archives of Biochemistry and Biophysics·E CsuhaiL B Hersh
Jan 5, 2001·Journal of Medicinal Chemistry·R A Casero, P M Woster
Jan 6, 2021·Langmuir : the ACS Journal of Surfaces and Colloids·Wenjing MaHongsheng Lu
Aug 24, 2007·Journal of the American Chemical Society·Michael D PluthKenneth N Raymond

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