Multifunctional, Fluorene‐Based Modulator of Cholinergic and GABAergic Neurotransmission as a Novel Drug Candidate for Palliative Treatment of Alzheimer's Disease
Abstract Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and behavioral and psychological symptoms of dementia (BPSD). Given that cholinergic neurons are predominantly affected in AD, current treatments primarily aim to enhance cholinergic neurotransmission. However, imbalances in other neurotransmitters, such as γ‐aminobutyric acid (GABA), also contribute to AD symptomatology. In the presented research, using a combination of crystallography and computational methods we developed compound 6 as a dual modulator of GABAergic and cholinergic neurotransmission systems. Compound 6 demonstrated inhibition of BuChE (IC 50 =0.21 μM) and GABA transporter 1 (IC 50 =10.96 μM) and 3 (IC 50 =7.76 μM), along with a favorable drug‐likeness profile. Subsequent in vivo studies revealed the effectiveness of 6 in enhancing memory retention and alleviating anxiety and depression symptoms in animal models, while also proving safe and bioavailable for oral administration. The innovative multi‐target‐directed ligand 6 offers a new approach to treating cognitive deficits and BPSD in AD.
Authors
- Nela Váňová (ORCID: https://orcid.org/0000-0002-1827-9308)
- Małgorzata Wolak (ORCID: https://orcid.org/0000-0002-3161-0878)
- Ondřej Soukup (ORCID: https://orcid.org/0000-0001-6376-8701)
- Florian Nachon (ORCID: https://orcid.org/0000-0003-0293-2429)
- Xavier Brazzolotto (ORCID: https://orcid.org/0000-0001-9219-1032)
- Dawid Panek (ORCID: https://orcid.org/0000-0002-3211-7188)
- Aleš Šorf (ORCID: https://orcid.org/0000-0001-7829-3980)
- Ľubica Múčková (ORCID: https://orcid.org/0000-0001-6693-6061)
- Anna Pasieka (ORCID: https://orcid.org/0000-0002-5426-9123)
- Jaroslav Pejchal (ORCID: https://orcid.org/0000-0003-2228-7922)
- Anna Więckowska (ORCID: https://orcid.org/0000-0003-2549-170X)
- Jakub Jończyk (ORCID: https://orcid.org/0000-0002-9731-908X)
- Marie Hamsikova
- Martin Mžik (ORCID: https://orcid.org/0000-0003-4649-7828)
- Agata Siwek (ORCID: https://orcid.org/0000-0001-5321-9266)
- Lukáš Prchal (ORCID: https://orcid.org/0000-0001-9698-4478)
- Barbara Mordyl (ORCID: https://orcid.org/0000-0001-7906-0353)
- Klaus T. Wanner (ORCID: https://orcid.org/0000-0003-4399-1425)
- Jana Žďárová Karasová (ORCID: https://orcid.org/0000-0003-0891-9591)
- Parker Dryja
- Fabien Chantegreil (ORCID: https://orcid.org/0000-0001-5982-8265)
- Georg Höfner
- Kinga Sałat (ORCID: https://orcid.org/0000-0003-0614-5393)
- Vít Šesták (ORCID: https://orcid.org/0000-0002-4688-2577)
- Lucie Zemanová (ORCID: https://orcid.org/0000-0002-2732-5935)
- Paula Zaręba (ORCID: https://orcid.org/0000-0002-5037-6183)
- Barbara Malawska (ORCID: https://orcid.org/0000-0003-4637-5820)
- Gniewomir Latacz (ORCID: https://orcid.org/0000-0001-9247-2598)
- Jan Korábečný (ORCID: https://orcid.org/0000-0001-6977-7596)
- Monika Głuch‐Lutwin (ORCID: https://orcid.org/0000-0003-1632-6569)
- Jitka Odvarkova (ORCID: https://orcid.org/0009-0009-0628-9865)
- Milena Gawlińska
Institutions
- Jagiellonian University (PL)
- Charles University (CZ)
- Institut de Médecine Tropicale du Service de Santé des Armées (FR)
- University Hospital Hradec Králové (CZ)
- University of Defence (RS)
- University of Hradec Králové (CZ)
- Ludwig-Maximilians-Universität München (DE)
- University of Defence (CZ)
Publication Details
- Journal
- Angewandte Chemie
- Published
- 2024-11-11
- DOI
- https://doi.org/10.1002/ange.202420510
- Primary Topic
- Cholinesterase and Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Univerzita Karlova v Praze
- Univerzita Hradec Králové
- Grantová Agentura České Republiky
- Ministerstvo Zdravotnictví Ceské Republiky
- Narodowe Centrum Nauki
- Ministerstvo Obrany České Republiky
- Ministère des Armées