Multifunctional, Fluorene-Based Modulator of Cholinergic and GABAergic Neurotransmission as a Novel Drug Candidate for Palliative Treatment of Alzheimer’s Disease

Dr. Dawid Panek, Dr. Anna Pasieka, Dr. Jakub Jończyk, Milena Gawlińska, Dr. Paula Zaręba, Dr. Agata Siwek, Dr. Małgorzata Wolak, Dr. Barbara Mordyl, Dr. Monika Głuch-Lutwin, Dr. Gniewomir Latacz, Dr. Xavier Brazzolotto, Dr. Fabien Chantegreil, Dr. Florian Nachon, Prof. Dr. Jana Zdarova Karasova, Dr. Jaroslav Pejchal, Dr. Martin Mzik, Dr. Vit Sestak, Lukas Prchal, Dr. Jitka Odvarkova, Dr. Ondrej Soukup, Prof. Dr. Jan Korabecny, Dr. Ales Sorf, Dr. Marie Hamsikova, Dr. Lucie Zemanova, Dr. Lubica Muckova, Dr. Nela Vánova, Pola Dryja, Prof. Dr. Kinga Sałat, Dr. Georg Höfner, Prof. Dr. Klaus Wanner, Dr. Anna Więckowska, Prof. Dr. Barbara Malawska

Progressive cognitive decline characterizing Alzheimer’s disease (AD) includes memory impairments and various behavioral and psychological symptoms of dementia (BPSD). Treatments traditionally target the predominantly affected cholinergic neurons to boost neurotransmission. However, dysfunctions in additional neurotransmitters such as γ-aminobutyric acid (GABA) also significantly influence AD’s clinical manifestations. This research introduces compound 6, developed through a blend of crystallography and computational analytics, serving as a dual regulator of GABAergic and cholinergic transmission. It effectively inhibits BuChE (IC50=0.21 μM) and GABA transporters 1 (IC50=10.96 μM) and 3 (IC50=7.76 μM), with a robust profile suitable for drug development. Compound 6’s efficacy in improving memory retention and mitigating symptoms of anxiety and depression was confirmed through in vivo tests, showing it to be safe and orally bioavailable. Offering a novel, multi-targeted therapeutic strategy, compound 6 holds potential for managing cognitive deficits and BPSD in Alzheimer’s disease.

DOI: 10.1002/anie.202420510