Structure-Activity Studies of 3,9-Diazaspiro[5.5]undecane-Based γ-Aminobutyric Acid Type A Receptor Antagonists with Immunomodulatory Effect

• Published in: Journal of medicinal chemistry Vol. 64; no. 24; pp. 17795 - 17812
• Main Authors: Bavo, Francesco, De-Jong, Heleen, Petersen, Jonas, Falk-Petersen, Christina Birkedahl, Loeffler, Rebekka, Sparrow, Emma, Rostrup, Frederik, Eliasen, Jannik Nicklas, Wilhelmsen, Kristine S., Barslund, Kasper, Bundgaard, Christoffer, Nielsen, Birgitte, Kristiansen, Uffe, Wellendorph, Petrine, Bogdanov, Yury, Frolund, Bente
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 23.12.2021
• Subjects: Adjuvants, Immunologic - chemistry; Adjuvants, Immunologic - pharmacology; Alkanes - chemistry; Alkanes - pharmacology; Cell Proliferation - drug effects; Chemistry, Medicinal; GABA Antagonists - chemistry; GABA Antagonists - pharmacology; Humans; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Receptors, GABA-A - drug effects; Science & Technology; Structure-Activity Relationship; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; 4-(PIPERIDIN-4-YL)-1-HYDROXYPYRAZOLES; DESIGN; PROTEIN; AFFINITY; SUBTYPES; PHARMACOLOGY; 3-ISOXAZOLOL GABA(A) ANTAGONISTS; ORTHOSTERIC BINDING-SITE; BRAIN; AGONIST
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00290

The 3,9-diazaspiro[5.5]undecane-based compounds 2027 and 018 have previously been reported to be potent competitive gamma-aminobutyric acid type A receptor (GABAAR) antagonists showing low cellular membrane permeability. Given the emerging peripheral application of GABAAR ligands, we hypothesize 2027 analogs as promising lead structures for peripheral GABAAR inhibition. We herein report a study on the structural determinants of 2027 in order to suggest a potential binding mode as a basis for rational design. The study identified the importance of the spirocyclic benzamide, compensating for the conventional acidic moiety, for GABAAR ligands. The structurally simplified m-methylphenyl analog 1e displayed binding affinity in the high-nanomolar range (Ki = 180 nM) and was superior to 2027 and 018 regarding selectivity for the extrasynaptic alpha 4 beta delta subtype versus the alpha 1- and alpha 2- containing subtypes. Importantly, 1e was shown to efficiently rescue inhibition of T cell proliferation, providing a platform to explore the immunomodulatory potential for this class of compounds.