eprintid: 10203788 rev_number: 9 eprint_status: archive userid: 699 dir: disk0/10/20/37/88 datestamp: 2025-01-22 11:39:20 lastmod: 2025-01-22 11:39:20 status_changed: 2025-01-22 11:39:20 type: article metadata_visibility: show sword_depositor: 699 creators_name: Xu, Yue creators_name: Mortensen, Martin creators_name: Liebowitz, Seth creators_name: Jensen, Nicoline N creators_name: Tian, Yongsong creators_name: Bavo, Francesco creators_name: Seidel, Thomas creators_name: Smart, Trevor G creators_name: Frølund, Bente title: Design, Synthesis, and Pharmacological Evaluation of Nonsteroidal Tricyclic Ligands as Modulators of GABAA Receptors ispublished: inpress divisions: UCL divisions: B02 divisions: C08 divisions: D09 divisions: G02 note: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions. abstract: GABAA receptors (GABAARs) are the major elements of inhibitory neurotransmission in the central nervous system (CNS). They are established targets for regulation by endogenous brain neuroactive steroids (NASs) such as pregnanolone. However, the complexity of de novo synthesis of NAS derivatives has hindered attempts to circumvent the principal limitations of using endogenous NASs, including selectivity and limited oral bioavailability. In this study, we designed a series of tricyclic compounds, inspired by the structures of pregnanolone and pregnenolone sulfate, to explore novel nonsteroidal alternatives. Using patch clamp electrophysiology, we demonstrate that these compounds exhibit either positive or negative allosteric modulation of GABAARs. Specifically, we discover a positive allosteric modulator (PAM) and a series of tricyclic sulfate-based negative allosteric modulators (NAMs) all active at the micromolar level. This research has significantly broadened the chemical diversity of ligands targeting GABAARs offering potential for efficacious allosteric modulators while avoiding the complexity of NAS synthesis. date: 2025-01-14 date_type: published publisher: American Chemical Society (ACS) official_url: https://doi.org/10.1021/acs.jmedchem.4c02881 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 2354126 doi: 10.1021/acs.jmedchem.4c02881 medium: Print-Electronic lyricists_name: Smart, Trevor lyricists_id: TSMAR12 actors_name: Smart, Trevor actors_id: TSMAR12 actors_role: owner full_text_status: restricted publication: Journal of Medicinal Chemistry event_location: United States citation: Xu, Yue; Mortensen, Martin; Liebowitz, Seth; Jensen, Nicoline N; Tian, Yongsong; Bavo, Francesco; Seidel, Thomas; ... Frølund, Bente; + view all <#> Xu, Yue; Mortensen, Martin; Liebowitz, Seth; Jensen, Nicoline N; Tian, Yongsong; Bavo, Francesco; Seidel, Thomas; Smart, Trevor G; Frølund, Bente; - view fewer <#> (2025) Design, Synthesis, and Pharmacological Evaluation of Nonsteroidal Tricyclic Ligands as Modulators of GABAA Receptors. Journal of Medicinal Chemistry 10.1021/acs.jmedchem.4c02881 <https://doi.org/10.1021/acs.jmedchem.4c02881>. (In press). Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10203788/3/Smart_Design%2C%20Synthesis%2C%20and%20Pharmacological%20Evaluation%20of%20Nonsteroidal%20Tricyclic%20Ligands%20as%20Modulators%20of%20GABAA%20Receptors_AAM.pdf