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Phosphinic,phosphonic and seleninic acid bioisosteres of isonipecotic acid as novel and selective GABA(C) receptor antagonists |
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| Authors: | Krehan Dorte Frølund Bente Krogsgaard-Larsen Povl Kehler Jan Johnston Graham A R Chebib Mary |
| Institution: | a Centre for Drug Design and Transport, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100, Copenhagen, Denmark b Department of Medicinal Chemistry, H. Lundbeck A/S, DK-2500, Valby, Denmark c Adrien Albert Laboratory of Medicinal Chemistry, Department of Pharmacology, The University of Sydney, Sydney, NSW 2006, Australia d Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia |
| Abstract: | A number of amino acids bioisosterically derived from the specific GABAA agonist, isonipecotic acid, were electrophysiologically characterized as antagonists at GABAC ρ1 receptors expressed in Xenopus oocytes. The phosphinic acid analogue of isonipecotic acid, piperidin-4-ylphosphinic acid (2), was comparable with the standard GABAC antagonist, (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA), in terms of potency and GABAC versus GABAA receptor selectivity. Whereas the phosphonic acid analogue, piperidin-4-ylphosphonic acid (4), was at least an order of magnitude weaker than piperidin-4-ylphosphinic acid as a GABAC antagonist, the seleninic acid analogue, piperidin-4-ylseleninic acid (SEPI, 6), was the most potent and selective GABAC antagonist within the group of isonipecotic acid derived amino acids studied. |
| Keywords: | GABAC receptors Homomeric receptors GABAC antagonists Bioisosteres Isonipecotic acid isosteres Electrophysiology Xenopus oocytes |
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