TY - JOUR

T1 - 5-(Piperidin-4-yl)-3-Hydroxypyrazole: A Novel Scaffold for Probing the Orthosteric γ-Aminobutyric Acid Type A Receptor Binding Site

AU - Krall, Jacob

AU - Kongstad, Kenneth Thermann

AU - Nielsen, Birgitte

AU - Sørensen, Troels Ersted

AU - Balle, Thomas

AU - Jensen, Anders A.

AU - Frølund, Bente

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

U2 - 10.1002/cmdc.201402248

DO - 10.1002/cmdc.201402248

M3 - Journal article

VL - 9

SP - 2475

EP - 2485

JO - Farmaco

JF - Farmaco

SN - 1860-7179

IS - 11

ER -