title: 5-(Piperidin-4-yl)-3-hydroxypyrazole: A novel scaffold for probing the orthosteric γ-aminobutyric acid type A receptor binding site.
abstract: A series of bioisosteric N1- and N2 -substituted 5-(piperidin-4-yl)-3-hydroxypyrazole analogues of the partial GABAA R agonists 4-PIOL and 4-PHP have been designed, synthesized, and characterized pharmacologically. The unsubstituted 3-hydroxypyrazole analogue of 4-PIOL (2 a; IC50 ∼300 μM) is a weak antagonist at the α1 β2 γ2 GABAA R, whereas substituting the N1- or N2- position with alkyl or aryl substituents resulted in antagonists with binding affinities in the high nanomolar to low micromolar range at native rat GABAA Rs. Docking studies using a α1 β2 γ2 GABAA R homology model along with the obtained SAR indicate that the N1 -substituted analogues of 4-PIOL and 4-PHP, 2 a-k, and previously reported 3-substituted 4-PHP analogues share a common binding mode to the orthosteric binding site in the receptor. Interestingly, the core scaffold of the N2 -substituted analogues of 4-PIOL and 4-PHP, 3 b-k, are suggested to flip 180° thereby adapting to the binding pocket and addressing a cavity situated above the core scaffold.
authors.affiliation: Department of Drug Design & Pharmacology, Faculty of Health and Medical Sciences, Universitetsparken 2, 2100 Copenhagen (Denmark).
authors.forename: Jacob
authors.initials: J
authors.lastname: Krall
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: Kongstad
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Troels E
authors.initials: TE
authors.lastname: Sørensen
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; D001665:Binding Sites; D058785:GABA-A Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007700:Kinetics; D062105:Molecular Docking Simulation; D010880:Piperidines / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D058785:GABA-A Receptor Agonists; D010880:Piperidines; D011720:Pyrazoles; D011963:Receptors, GABA-A
keywords: 3-hydroxypyrazoles; GABAA receptor; antagonists; bioisosteres; structure-activity relationships