Dual Piperidine-Based Histamine H3 and Sigma-1 Receptor Ligands in the Treatment of Nociceptive and Neuropathic Pain PMID: 37418295

ADC Targets in Oncology

2026-04-10

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

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.

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.