2. Academic Validation
  3. 4-Oxypiperidine Ethers as Multiple Targeting Ligands at Histamine H3 Receptors and Cholinesterases

4-Oxypiperidine Ethers as Multiple Targeting Ligands at Histamine H3 Receptors and Cholinesterases

  • ACS Chem Neurosci. 2024 Mar 5. doi: 10.1021/acschemneuro.3c00800.
Beata Michalska 1,  Marek Dzięgielewski 1,  Justyna Godyń 2,  Tobias Werner 3,  Marek Bajda 2,  Tadeusz Karcz 4,  Katarzyna Szczepańska 4 5,  Holger Stark 3,  Anna Więckowska 2,  Krzysztof Walczyński 1,  Marek Staszewski 1
Affiliations

Affiliations

  • 1 Department of Synthesis and Technology of Drugs, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland.
  • 2 Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
  • 3 Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany.
  • 4 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
  • 5 Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland.
PMID: 38440987 DOI: 10.1021/acschemneuro.3c00800
Abstract

This study examines the properties of a novel series of 4-oxypiperidines designed and synthesized as histamine H3R antagonists/inverse agonists based on the structural modification of two lead compounds, viz., ADS003 and ADS009. The products are intended to maintain a high affinity for H3R while simultaneously inhibiting AChE or/and BuChE enzymes. Selected compounds were subjected to hH3R radioligand displacement and gpH3R functional assays. Some of the compounds showed nanomolar affinity. The most promising compound in the naphthalene series was ADS031, which contained a benzyl moiety at position 1 of the piperidine ring and displayed 12.5 nM affinity at the hH3R and the highest inhibitory activity against AChE (IC50 = 1.537 μM). Eight compounds showed over 60% eqBuChE inhibition and hence were qualified for the determination of the IC50 value at eqBuChE; their values ranged from 0.559 to 2.655 μM. Therapy based on a multitarget-directed ligand combining H3R antagonism with additional AChE/BuChE inhibitory properties might improve cognitive functions in multifactorial Alzheimer's disease.

Keywords

acetylcholinestrase inhibitor; butyrylcholinesterase inhibitor; histamine H3 receptor; multiple targeting; neurodegenerative disease; polypharmacology.

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