5-(Piperidin-4-yl)-3-Hydroxypyrazole: A Novel Scaffold for Probing the Orthosteric γ-Aminobutyric Acid Type A Receptor Binding Site
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A series of bioisosteric N1- and N2-substituted 5-(piperidin-4-yl)-3-hydroxypyrazole analogues of the partial GABAAR 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 α1β2γ2 GABAAR, 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 GABAARs. Docking studies using a α1β2γ2 GABAAR 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.
Original language | English |
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Journal | ChemMedChem |
Volume | 9 |
Issue number | 11 |
Pages (from-to) | 2475-2485 |
Number of pages | 11 |
ISSN | 1860-7179 |
DOIs | |
Publication status | Published - 2014 |
ID: 118590743