title: Activity of novel 4-PIOL analogues at human alpha 1 beta 2 gamma 2S GABA(A) receptors--correlation with hydrophobicity.
abstract: A series of novel 5-(4-piperidyl)-3-isoxazolol (4-PIOL) analogues where the 4-position of the 3-isoxazolol ring was substituted with groups of different size, flexibility, and lipophilicity have been characterised. Their activity as agonists and/or antagonists on human alpha(1)beta(2)gamma(2S) GABA(A) receptors expressed in Xenopus oocytes was studied using two-electrode voltage clamp electrophysiology. Methyl- and ethyl-substituted 4-PIOL analogues were characterised as partial agonists since weak agonist responses could be potentiated with lorazepam and inhibited by the competitive antagonist 2-(3-carboxypropyl)-3-amino-6-methoxyphenyl-pyradizinum bromide (SR95531). All larger substituents in the 4-position of the 3-isoxazolol ring of 4-PIOL converted the compounds into pure competitive antagonists. Additionally, for GABA, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), piperidine-4-sulphonic acid (P4S), and 5-(4-piperidyl)-3-isothiazolol (thio-4-PIOL), a negative linear correlation was found between the agonist efficacy of the compound and the ability of lorazepam to potentiate EC(95) responses. Furthermore, a positive linear correlation between the lipophilicity of the substituents in the 4-position of the 3-isoxazolol ring of 4-PIOL and the antagonist affinity was found. These data suggest that the GABA(A) receptor contains a hydrophobic binding pocket at the GABA recognition site and that the binding of the 4-PIOL analogues is largely determined by the transfer from the aqueous phase to the hydrophobic pocket.
authors.affiliation: Department of Pharmacology, The Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Mortensen
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
authors.forename: Anne T
authors.initials: AT
authors.lastname: Jørgensen
authors.forename: Tommy
authors.initials: T
authors.lastname: Liljefors
authors.forename: Povl
authors.initials: P
authors.lastname: Krogsgaard-Larsen
authors.forename: Bjarke
authors.initials: B
authors.lastname: Ebert
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D058785:GABA-A Receptor Agonists; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000096:biosynthesis; D014982:Xenopus laevis
chemical_list: D058785:GABA-A Receptor Agonists; D007555:Isoxazoles; D010880:Piperidines; D011963:Receptors, GABA-A; C073009:5-(4-piperidyl)isoxazol-3-ol