Structural determinants of activity at the GABAB receptor. A comparison of phosphoethanolamine and related GABA analogs

Molecular and Chemical Neuropathology
W E KlunkJ W Pettegrew

Abstract

Phosphoethanolamine is a phosphomonoester that is reduced in Alzheimer disease brain. Despite its close structural similarity to GABA and the GABAB partial agonist 3-aminopropylphosphonic acid, phosphoethanolamine binds very poorly to GABAB receptors (IC50 = 7.5 +/- 0.8 mM). In this study, we examined whether the marked decrease in binding affinity associated with the presence of an ester oxygen in place of the alpha-CH2 group of GABAergic compounds also occurred in sulfonates and used high resolution solution NMR and molecular mechanics calculations to determine the structural basis of this decrease in activity. The sulfonate analog of GABA, 3-amino-propylsulfonic acid, became > 2500-fold less potent when the alpha-CH2 was replaced by an ester oxygen. Structural studies showed that the active alpha-CH2 compounds (GABA, 3-aminopropylphosphonic acid, and 3-aminopropylsulfonic acid) prefer a fully extended conformation. The inactive compounds, phosphoethanolamine and ethanolamine-O-sulfate, exist in a gauche conformation around the C beta-C gamma bond. This study, which suggests conformational differences, may explain how PE can be so efficiently excluded from GABAB receptors, despite being present in millimolar concentrations in...Continue Reading

Citations

Jan 23, 1998·Molecular and Chemical Neuropathology·C J XuJ W Pettegrew
May 1, 1996·Neurobiology of Aging·W E KlunkJ W Pettegrew
Jan 4, 2001·Brain Research Bulletin·J W PettegrewJ A Stanley
Jan 23, 2018·Psychiatry and Clinical Neurosciences·Noriyuki KawamuraYoshiaki Ohashi
Nov 5, 1997·Annals of the New York Academy of Sciences·J W PettegrewJ A Stanley

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