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

Navnath Gavande; Izumi Yamamoto; Noeris K Salam; Tu-Hoa Ai; Peter M Burden; Graham A R Johnston; Jane R Hanrahan; Mary Chebib

doi:10.1021/ml1001344

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

ACS Med Chem Lett. 2010 Oct 19;2(1):11-6. doi: 10.1021/ml1001344. eCollection 2011 Jan 13.

Authors

Navnath Gavande¹, Izumi Yamamoto¹, Noeris K Salam², Tu-Hoa Ai³, Peter M Burden³, Graham A R Johnston³, Jane R Hanrahan¹, Mary Chebib¹

Affiliations

¹ Faculty of Pharmacy, The University of Sydney, NSW, Australia.
² Schrodinger, Inc., 8910 University Center Lane, Suite 270, San Diego, California, United States.
³ Adrien Albert Laboratory, Department of Pharmacology, The University of Sydney, NSW, Australia.

Abstract

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, K B = 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.

Keywords: GABA receptors; cyclic phosphinic acids; ligand-gated ion channels; two-electrode voltage clamp; γ-Aminobutyric acid; ρ1 GABAC homology model.