title: Novel 4-(piperidin-4-yl)-1-hydroxypyrazoles as gamma-aminobutyric acid(A) receptor ligands: synthesis, pharmacology, and structure-activity relationships.
abstract: A series of substituted 1-hydroxypyrazole analogues of the GABA(A) receptor partial agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL) have been synthesized and pharmacologically characterized. Several of the analogues displayed K(i) in the low nanomolar range at the native GABA(A) receptors and potent antagonism of the alpha(1)beta(2)gamma(2) receptor. It appears that several regions situated in proximity to the core of the orthosteric binding site of the GABA(A) receptor are able to accommodate large hydrophobic substituents.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, DK 2100 Copenhagen.
authors.forename: Henriette A
authors.initials: HA
authors.lastname: Møller
authors.forename: Tommy
authors.initials: T
authors.lastname: Sander
authors.forename: Jesper L
authors.initials: JL
authors.lastname: Kristensen
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Jacob
authors.initials: J
authors.lastname: Krall
authors.forename: Marianne L
authors.initials: ML
authors.lastname: Bergmann
authors.forename: Bolette
authors.initials: B
authors.lastname: Christiansen
authors.forename: Thomas
authors.initials: T
authors.lastname: Balle
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
mesh_terms: D000818:Animals; D002460:Cell Line; D018756:GABA Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058805:GABA Uptake Inhibitors; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013570:Synaptic Membranes / Q000187:drug effects / Q000502:physiology
chemical_list: D018756:GABA Antagonists; D058805:GABA Uptake Inhibitors; D008024:Ligands; D010880:Piperidines; D011720:Pyrazoles; D011963:Receptors, GABA-A