title: Phosphinic, phosphonic and seleninic acid bioisosteres of isonipecotic acid as novel and selective GABA(C) receptor antagonists.
abstract: A number of amino acids bioisosterically derived from the specific GABA(A) agonist, isonipecotic acid, were electrophysiologically characterized as antagonists at GABA(C) rho(1) receptors expressed in Xenopus oocytes. The phosphinic acid analogue of isonipecotic acid, piperidin-4-ylphosphinic acid (2), was comparable with the standard GABA(C) antagonist, (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA), in terms of potency and GABA(C) versus GABA(A) 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 GABA(C) antagonist, the seleninic acid analogue, piperidin-4-ylseleninic acid (SEPI, 6), was the most potent and selective GABA(C) antagonist within the group of isonipecotic acid derived amino acids studied.
authors.affiliation: Centre for Drug Design and Transport, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
authors.forename: Dorte
authors.initials: D
authors.lastname: Krehan
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
authors.forename: Povl
authors.initials: P
authors.lastname: Krogsgaard-Larsen
authors.forename: Jan
authors.initials: J
authors.lastname: Kehler
authors.forename: Graham A R
authors.initials: GA
authors.lastname: Johnston
authors.forename: Mary
authors.initials: M
authors.lastname: Chebib
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology*; D006801:Humans; D007540:Isonipecotic Acids / Q000737:chemistry*; D009865:Oocytes; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology*; D016566:Organoselenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D010721:Phosphinic Acids / Q000737:chemistry / Q000494:pharmacology*; D020033:Protein Isoforms / Q000187:drug effects; D018079:Receptors, GABA / Q000187:drug effects*; D014982:Xenopus laevis
chemical_list: D002264:Carboxylic Acids; D018756:GABA Antagonists; C087200:GABA-C receptor; D007540:Isonipecotic Acids; D063065:Organophosphonates; D016566:Organoselenium Compounds; D010721:Phosphinic Acids; D020033:Protein Isoforms; D018079:Receptors, GABA; C473453:seleninic acid