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

• Published in: ChemMedChem 2014-11, Vol.9 (11), p.2475-2485
• Main Authors: Krall, Jacob, Kongstad, Kenneth T., Nielsen, Birgitte, Sørensen, Troels E., Balle, Thomas, Jensen, Anders A., Frølund, Bente
• Format: Article
• Language: English
• Subjects: 3-hydroxypyrazoles; Animals; antagonists; Binding Sites; bioisosteres; GABA-A Receptor Agonists - chemical synthesis; GABA-A Receptor Agonists - chemistry; GABA-A Receptor Agonists - metabolism; GABAA receptor; Inhibitory Concentration 50; Kinetics; Molecular Docking Simulation; Piperidines - chemistry; Protein Structure, Tertiary; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - metabolism; Rats; Receptors, GABA-A - chemistry; Receptors, GABA-A - metabolism; Structure-Activity Relationship; structure-activity relationships
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201402248

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. Exploring hydrophobic cavities in the vicinity of the GABAAR binding site leads to novel antagonists. Increasing the hydrophobicity of the N1‐ or N2‐substituents of a new GABAA receptor antagonist scaffold results in a similar SAR between the compound series. However, docking studies suggest different binding modes for the two series in the GABAA receptor binding site.