title: Exploring the orthosteric binding site of the γ-aminobutyric acid type A receptor using 4-(Piperidin-4-yl)-1-hydroxypyrazoles 3- or 5-imidazolyl substituted: design, synthesis, and pharmacological evaluation.
abstract: A series of 4-(piperidin-4-yl)-1-hydroxypyrazole (4-PHP) 3- or 5-imidazolyl substituted analogues have been designed, synthesized, and characterized pharmacologically. All analogues showed binding affinities in the low micro- to low nanomolar range at native rat GABAA receptors and were found to be antagonists at the human α1β2γ2s receptor. The structure-activity relationship of the compound series demonstrates distinct differences in size and architecture of previously discovered cavities in the vicinity of the 4-PHP scaffold in the orthosteric binding site.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Krall
authors.forename: Claus H
authors.initials: CH
authors.lastname: Jensen
authors.forename: Troels E
authors.initials: TE
authors.lastname: Sørensen
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
authors.forename: Tommy
authors.initials: T
authors.lastname: Sander
authors.forename: Thomas
authors.initials: T
authors.lastname: Balle
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
mesh_terms: D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D011720:Pyrazoles; D011963:Receptors, GABA-A