5‐(Piperidin‐4‐yl)‐3‐Hydroxypyrazole: A Novel Scaffold for Probing the Orthosteric γ‐Aminobutyric Acid Type A Receptor Binding Site. Issue 11 (26th August 2014)

• Record Type: Journal Article
• Authors: Krall, Jacob; Kongstad, Kenneth T.; Nielsen, Birgitte; Sørensen, Troels E.; Balle, Thomas; Jensen, Anders A.; Frølund, Bente
• Is Part Of: ChemMedChem. Volume 9:Issue 11(2014:Nov.)
• Page Start: 2475
• Page End: 2485
• Publication Date: 2014-08-26
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201402248
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>A series of bioisosteric <italic>N</italic>₁‐ and <italic>N</italic>₂‐substituted 5‐(piperidin‐4‐yl)‐3‐hydroxypyrazole analogues of the partial GABA_AR agonists 4‐PIOL and 4‐PHP have been designed, synthesized, and characterized pharmacologically. The unsubstituted 3‐hydroxypyrazole analogue of 4‐PIOL (<bold>2 a</bold>; IC₅₀∼300 μ<sc>M</sc>) is a weak antagonist at the α₁β₂γ₂ GABA_AR, whereas substituting the <italic>N</italic>₁‐ or <italic>N</italic>₂‐position with alkyl or aryl substituents resulted in antagonists with binding affinities in the high nanomolar to low micromolar range at native rat GABA_ARs. Docking studies using a α₁β₂γ₂ GABA_AR homology model along with the obtained SAR indicate that the <italic>N</italic>₁‐substituted analogues of 4‐PIOL and 4‐PHP, <bold>2 a</bold>–<bold>k</bold>, 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 <italic>N</italic>₂‐substituted analogues of 4‐PIOL and 4‐PHP, <bold>3 b</bold>–<bold>k</bold>, are suggested to flip 180° thereby adapting to the binding pocket and addressing a cavity situated above the core scaffold.</p> </abstract>