Novel Cyclic Phosphinic Acids as GABAC ρ Receptor Antagonists: Design Synthesis and Pharmacology

摘要

Understanding the role of GABAC receptors in the central nervous system is limited due to a lack of specific ligands. Novel γ-aminobutyric acid (GABA) analogues based on 3-(aminomethyl)-1-oxo-1-hydroxy-phospholane >17 and 3-(guanido)-1-oxo-1-hydroxy-phospholane >19 were investigated to obtain selective GABAC receptor antagonists. A compound of high potency (>19, KB = 10 μM) and selectivity (greater than 100 times at ρ1 GABAC receptors as compared to α1β2γ2L GABAA and GABAB(1b,2) receptors) was obtained. The cyclic phosphinic acids (>17 and >19) are novel lead agents for developing into more potent and selective GABAC receptor antagonists with increased lipophilicity for future in vivo studies.