STRUCTURAL DETERMINANTS OF ACTIVITY AT THE GABA(B) RECEPTOR - A COMPARISON OF PHOSPHOETHANOLAMINE AND RELATED GABA ANALOGS

Phosphoethanolamine is a phosphomonoester that is reduced in Alzheimer disease brain. Despite its close structural similarity to GABA and th e GABA(B) partial agonist 3-aminopropylphosphonic acid, phosphoethanol amine binds very poorly to GABA(B) receptors (IC50 = 7.5 +/- 0.8 mM). In this study, we examined whether the marked decrease in binding affi nity associated with the presence of an ester oxygen in place of the a lpha-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 s ulfonate analog of GABA, 3-aminopropylsulfonic acid, became > 2500-fol d less potent when the alpha-CH2 was replaced by an ester oxygen. Stru ctural studies showed that the active alpha-CH2 compounds (GABA, 3-ami nopropylphosphonic acid, and 3-aminopropylsulfonic acid) prefer a full y extended conformation. The inactive compounds, phosphoethanolamine a nd ethanolamine-O-sulfate, exist in a gauche conformation around the C -beta-C-gamma bond. This study, which suggests conformational differen ces, may explain how PE can be so efficiently excluded from GABA(B) re ceptors, despite being present in millimolar concentrations in brain. Exclusion of phosphoethanolamine from GABA(B) receptors may be an impo rtant physiologic control mechanism in the regulation of inhibitory ne urotransmission.