Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H3 and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties.

Katarzyna Szczepańska,Enrique J Cobos,Denise Mönnich,Agata Siwek,Steffen Pockes,Andrzej J Bojarski,Sabina Podlewska,Katarzyna Kieć-Kononowicz,Ma Carmen Ruiz Cantero,Davide Gentile,Agostino Marrazzo,Vincenzo Patamia,Antonio Rescifina,Holger Stark,Emanuele Amata,Maria Dichiara,Dorota Łażewska,Tadeusz Karcz,Niklas Rosier

doi:10.1021/acschemneuro.1c00435

Abstract

In an attempt to extend recent studies showing that some clinically evaluated histamine H3 receptor (H3R) antagonists possess nanomolar affinity at sigma-1 receptors (σ1R), we selected 20 representative structures among our previously reported H3R ligands to investigate their affinity at σRs. Most of the tested compounds interact with both sigma receptors to different degrees. However, only six of them showed higher affinity toward σ1R than σ2R with the highest binding preference to σ1R for compounds 5, 11, and 12. Moreover, all these ligands share a common structural feature: the piperidine moiety as the fundamental part of the molecule. It is most likely a critical structural element for dual H3/σ1 receptor activity as can be seen by comparing the data for compounds 4 and 5 (hH3R Ki = 3.17 and 7.70 nM, σ1R Ki = 1531 and 3.64 nM, respectively), where piperidine is replaced by piperazine. We identified the putative protein–ligand interactions responsible for their high affinity using molecular modeling techniques and selected compounds 5 and 11 as lead structures for further evaluation. Interestingly, both ligands turned out to be high-affinity histamine H3 and σ1 receptor antagonists with negligible affinity at the other histamine receptor subtypes and promising antinociceptive activity in vivo. Considering that many literature data clearly indicate high preclinical efficacy of individual selective σ1 or H3R ligands in various pain models, our research might be a breakthrough in the search for novel, dual-acting compounds that can improve existing pain therapies. Determining whether such ligands are more effective than single-selective drugs will be the subject of our future studies.

Highlights

In recent decades, significant research efforts have been invested in discovering and developing therapeutics that modulate individual disease-modifying targets
Multicomponent drugs are standard in therapeutic areas such as cancer, diabetes, and psychiatric or degenerative central nervous system (CNS) disorders, paradoxically composed of agents initially developed as single-target drugs.[3,4]
Replacing the piperazine ring with piperidine did not significantly affect the affinity at H3 receptor (H3R), which can be deduced by comparing data from compounds 4 and 5

Summary

Introduction

Significant research efforts have been invested in discovering and developing therapeutics that modulate individual disease-modifying targets. This approach has led to growth in the industry and numerous successful drugs reaching the market, only a few new drugs act at novel molecular targets. The limitations of many monotherapies can be overcome by attacking the disease system on multiple fronts.[1] Multitarget therapeutics may be more effective and less vulnerable to adaptive resistance because the biological system is less able to compensate for the effects of two or more drugs simultaneously.[2] multicomponent drugs are standard in therapeutic areas such as cancer, diabetes, and psychiatric or degenerative central nervous system (CNS) disorders, paradoxically composed of agents initially developed as single-target drugs.[3,4]. They have been described as both presynaptic autoreceptors regulating the synthesis and release of histamine and heteroreceptors modulating the release of neurotransmitters such as acetylcholine, dopamine, norepinephrine, serotonin, γaminobutyric acid, glutamate, and substance P.6,7 Pharmacological data reveal potentially beneficial outcomes of H3R

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