2. Academic Validation
  3. Dual Piperidine-Based Histamine H3 and Sigma-1 Receptor Ligands in the Treatment of Nociceptive and Neuropathic Pain

Dual Piperidine-Based Histamine H3 and Sigma-1 Receptor Ligands in the Treatment of Nociceptive and Neuropathic Pain

  • J Med Chem. 2023 Jul 27;66(14):9658-9683. doi: 10.1021/acs.jmedchem.3c00430.
Katarzyna Szczepańska 1 2,  Tadeusz Karcz 1,  Maria Dichiara 3,  Szczepan Mogilski 4,  Justyna Kalinowska-Tłuścik 5,  Bogusław Pilarski 6,  Arkadiusz Leniak 7,  Wojciech Pietruś 2 7,  Sabina Podlewska 2,  Katarzyna Popiołek-Barczyk 8,  Laura J Humphrys 9,  M Carmen Ruiz-Cantero 10,  David Reiner-Link 11,  Luisa Leitzbach 11,  Dorota Łażewska 1,  Steffen Pockes 9,  Michał Górka 7,  Adam Zmysłowski 7,  Thierry Calmels 12,  Enrique J Cobos 10,  Agostino Marrazzo 3,  Holger Stark 11,  Andrzej J Bojarski 2,  Emanuele Amata 3,  Katarzyna Kieć-Kononowicz 1
Affiliations

Affiliations

  • 1 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
  • 2 Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.
  • 3 Department of Drug and Health Sciences, University of Catania, V.le A. Doria, 95125 Catania, Italy.
  • 4 Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
  • 5 Department of Crystal Chemistry and Crystal Physics, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Kraków, Poland.
  • 6 Cerko Sp. z o.o. Sp.k, Al. Zwycięstwa 96/98, 81-451 Gdynia, Poland.
  • 7 Celon Pharma S.A., R&D Centre, Marymoncka 15, 05-152 Kazuń Nowy, Poland.
  • 8 Department of Neurochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.
  • 9 Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
  • 10 Department of Pharmacology and Neurosciences Institute (Biomedical Research Center), University of Granada, and Biosanitary Research Institute ibs. Granada, Avenida de la Investigación 11, 18016 Granada, Spain.
  • 11 Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, 40225 Düsseldorf, Germany.
  • 12 Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France.
PMID: 37418295 DOI: 10.1021/acs.jmedchem.3c00430
Abstract

In search of new dual-acting histamine H3/sigma-1 receptor ligands, we designed a series of compounds structurally based on highly active in vivo ligands previously studied and described by our team. However, we kept in mind that within the previous series, a pair of closely related compounds, KSK67 and KSK68, differing only in the piperazine/piperidine moiety in the structural core showed a significantly different affinity at sigma-1 receptors (σ1Rs). Therefore, we first focused on an in-depth analysis of the protonation states of piperazine and piperidine derivatives in the studied compounds. In a series of 16 new ligands, mainly based on the piperidine core, we selected three lead structures (3, 7, and 12) for further biological evaluation. Compound 12 showed a broad spectrum of analgesic activity in both nociceptive and Neuropathic Pain Models based on the novel molecular mechanism.

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