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Pharmaceuticals
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Histamine Receptor Ligands in Medicinal Chemistry
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Histamine Receptor Ligands in Medicinal Chemistry

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 25 December 2024 | Viewed by 12349

Special Issue Editors

Prof. Dr. Krzysztof Walczyński

E-Mail Website
Guest Editor
Department of Synthesis and Technology of Drugs, Medical University of Lodz, ul. Muszyńskiego 1, 90-151 Łódź, Poland
Interests: medicinal chemistry; drug discovery; organic synthesis; heterocyclic synthesis; multi-target ligands; histamine; H3 ligands; H1 ligands; guinea pig ex vivo assay
Dr. Marek Staszewski

E-Mail Website
Guest Editor
Department of Synthesis and Technology of Drugs, Medical University of Lodz, ul. Muszyńskiego 1, 90-151 Łódź, Poland
Interests: medicinal chemistry; drug discovery; organic synthesis; heterocyclic synthesis; multi-target ligands; histamine; H3 ligands; H1 ligands; guinea pig ex vivo assay

Special Issue Information

Dear Colleagues,

Pharmacological studies have confirmed the existence of four histamine receptors. Histamine plays a pathophysiological role in allergy via H1R and a key physiological role in the control of gastric acid secretion via H2R. Both receptors remain valuable in the treatment of allergic diseases and duodenal ulcers. The marketed H3R antagonist is useful in narcolepsy, but further studies are investigating the use of H3R ligands in some CNS disorders, i.e., memory or learning deficits including Prader–Willi syndrome, or epilepsy and obesity, are investigated. H4R ligands are promising compounds that act on the immune system and have the potential to be used in asthma and inflammation. Certain histamine receptor ligands with additional pharmacological targets modulate acetylcholine, dopamine, norepinephrine, serotonin, γ-aminobutyric acid, dopamine levels, and even breast cancer cell proliferation, often leading to the discovery of multipotent compounds. Histamine and its receptors continue to be of interest to medicinal chemists and pharmacologists, and the recently described crystal structure of H3R may also increase the interest in the search for new ligands.

We encourage all scientists to contribute their research results on histamine receptors and their ligands to this Special Issue. Review papers are also welcome. The subtopics of a submitted manuscript may include, but are not limited to, the following:

  • The discovery and structural modification of histamine receptor ligands;
  • Target-based drug discovery;
  • The pharmacological or pharmacokinetic evaluation of potent histamine receptors ligands;
  • Alternative therapeutics: novelty and hopes;
  • Multifunctional histamine receptor ligands in medicinal chemistry;
  • Bio- and chemo-informatics, molecular modeling histamine receptors, and their ligands.

Prof. Dr. Krzysztof Walczyński
Dr. Marek Staszewski
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug discovery
  • histamine
  • receptors
  • biogenic amines
  • ligands
  • antagonist/inverse agonist
  • affinity/potency
  • intrinsic activity
  • pharmacological evaluation
  • pharmacokinetic evaluation
  • SAR
  • CNS diseases
  • anticancer ligands
  • allergy
  • neurodegeneration
  • cognitive functions
  • multitarget ligands
  • molecular modeling
  • in vitro studies
  • in silico studies
  • in vivo studies

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Published Papers (6 papers)

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Research

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19 pages, 7120 KiB  
Article
The Effect of KSK-94, a Dual Histamine H3 and Sigma-2 Receptor Ligand, on Adipose Tissue in a Rat Model of Developing Obesity
by Magdalena Kotańska, Monika Zadrożna, Monika Kubacka, Kamil Mika, Katarzyna Szczepańska, Barbara Nowak, Alessio Alesci, Anthea Miller, Eugenia Rita Lauriano and Katarzyna Kieć-Kononowicz
Pharmaceuticals 2024, 17(7), 858; https://doi.org/10.3390/ph17070858 - 1 Jul 2024
Viewed by 462
Abstract
Background: Numerous studies highlight the critical role that neural histamine plays in feeding behavior, which is controlled by central histamine H3 and H1 receptors. This is the fundamental motivation for the increased interest in creating histamine H3 receptor antagonists as [...] Read more.
Background: Numerous studies highlight the critical role that neural histamine plays in feeding behavior, which is controlled by central histamine H3 and H1 receptors. This is the fundamental motivation for the increased interest in creating histamine H3 receptor antagonists as anti-obesity medications. On the other hand, multiple other neurotransmitter systems have been identified as pharmacotherapeutic targets for obesity, including sigma-2 receptor systems. Interestingly, in our previous studies in the rat excessive eating model, we demonstrated a significant reduction in the development of obesity using dual histamine H3/sigma-2 receptor ligands. Moreover, we showed that compound KSK-94 (structural analog of Abbott’s A-331440) reduced the number of calories consumed, and thus acted as an anorectic compound. Therefore, in this study, we extended the previous research and studied the influence of KSK-94 on adipose tissue collected from animals from our previous experiment. Methods: Visceral adipose tissue was collected from four groups of rats (standard diet + vehicle, palatable diet + vehicle, palatable diet + KSK-94, and palatable diet + bupropion/naltrexone) and subjected to biochemical, histopathological, and immunohistochemical studies. Results: The obtained results clearly indicate that compound KSK-94 prevented the hypertrophy and inflammation of visceral adipose tissue, normalized the levels of leptin, resistin and saved the total reduction capacity of adipose tissue, being more effective than bupropion/naltrexon in these aspects. Moreover, KSK-94 may induce browning of visceral white adipose tissue. Conclusion: Our study suggests that dual compounds with a receptor profile like KSK-94, i.e., targeting histamine H3 receptor and, to a lesser extent, sigma-2 receptor, could be attractive therapeutic options for patients at risk of developing obesity or with obesity and some metabolic disorders. However, more studies are required to determine its safety profile and the exact mechanism of action of KSK-94. Full article
(This article belongs to the Special Issue Histamine Receptor Ligands in Medicinal Chemistry)
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13 pages, 1874 KiB  
Article
Effects of the DL76 Antagonist/Inverse Agonist of Histamine H3 Receptors on Experimental Periodontitis in Rats: Morphological Studies
by Mariusz Geremek, Bogna Drozdzowska, Dorota Łażewska, Katarzyna Kieć-Kononowicz and Jerzy Jochem
Pharmaceuticals 2024, 17(6), 792; https://doi.org/10.3390/ph17060792 - 17 Jun 2024
Viewed by 634
Abstract
Background: Periodontitis preceded by gingivitis is the most common form of periodontal disease and occurs due to the interaction of microorganisms present in the complex bacterial aggregates of dental plaque biofilm and their metabolism products with periodontal tissues. Histamine is a heterocyclic biogenic [...] Read more.
Background: Periodontitis preceded by gingivitis is the most common form of periodontal disease and occurs due to the interaction of microorganisms present in the complex bacterial aggregates of dental plaque biofilm and their metabolism products with periodontal tissues. Histamine is a heterocyclic biogenic amine acting via four types of receptors. Histamine H3 receptors act as presynaptic auto/heteroreceptors to regulate the release of histamine and other neurotransmitters. Aim: Since the nervous system is able to regulate the progression of the inflammatory process and bone metabolism, the aim of this study was to investigate the effects of DL76, which acts as an antagonist/inverse agonist of H3 receptors, on the course of experimental periodontitis. Materials and methods: This study was conducted in 24 mature male Wistar rats weighing 245–360 g, aged 6–8 weeks. A silk ligature was placed on the second maxillary molar of the right maxilla under general anesthesia. From the day of ligating, DL76 and 0.9% NaCl solutions were administered subcutaneously for 28 days in the experimental and control groups, respectively. After the experiment, histopathological, immunohistochemical and radiological examinations were performed. Results: Ligation led to the development of the inflammatory process with lymphocytic infiltration, increased epithelial RANKL and OPG expression as well as bone resorption. DL76 evoked a reduction in (1) lymphocytic infiltration, (2) RANKL and OPG expression as well as (3) bone resorption since the medians of the mesial and distal interdental spaces in the molars with induced periodontitis were 3.56-fold and 10-fold lower compared to the corresponding values in saline-treated animals with periodontitis. Conclusion: DL76 is able to inhibit the progression of experimental periodontitis in rats, as demonstrated by a reduction in the inflammatory cell infiltration, a decrease in the RANKL/RANK OPG pathway expression and a reduction in the alveolar bone resorption. Full article
(This article belongs to the Special Issue Histamine Receptor Ligands in Medicinal Chemistry)
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12 pages, 3522 KiB  
Article
Synthesis and Pharmacological Characterization of New Photocaged Agonists for Histamine H3 and H4 Receptors
by Yang Zheng, Meichun Gao, Maikel Wijtmans, Henry F. Vischer and Rob Leurs
Pharmaceuticals 2024, 17(4), 536; https://doi.org/10.3390/ph17040536 - 21 Apr 2024
Viewed by 1143
Abstract
The modulation of biological processes with light-sensitive chemical probes promises precise temporal and spatial control. Yet, the design and synthesis of suitable probes is a challenge for medicinal chemists. This article introduces a photocaging strategy designed to modulate the pharmacology of histamine H [...] Read more.
The modulation of biological processes with light-sensitive chemical probes promises precise temporal and spatial control. Yet, the design and synthesis of suitable probes is a challenge for medicinal chemists. This article introduces a photocaging strategy designed to modulate the pharmacology of histamine H3 receptors (H3R) and H4 receptors (H4R). Employing the photoremovable group BODIPY as the caging entity for two agonist scaffolds—immepip and 4-methylhistamine—for H3R and H4R, respectively, we synthesized two BODIPY-caged compounds, 5 (VUF25657) and 6 (VUF25678), demonstrating 10–100-fold reduction in affinity for their respective receptors. Notably, the caged H3R agonist, VUF25657, exhibits approximately a 100-fold reduction in functional activity. The photo-uncaging of VUF25657 at 560 nm resulted in the release of immepip, thereby restoring binding affinity and potency in functional assays. This approach presents a promising method to achieve optical control of H3R receptor pharmacology. Full article
(This article belongs to the Special Issue Histamine Receptor Ligands in Medicinal Chemistry)
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19 pages, 1849 KiB  
Article
Antioxidant and Anti-Glycation Potential of H2 Receptor Antagonists—In Vitro Studies and a Systematic Literature Review
by Grzegorz Biedrzycki, Blanka Wolszczak-Biedrzycka, Justyna Dorf, Daniel Michalak, Małgorzata Żendzian-Piotrowska, Anna Zalewska and Mateusz Maciejczyk
Pharmaceuticals 2023, 16(9), 1273; https://doi.org/10.3390/ph16091273 - 8 Sep 2023
Cited by 3 | Viewed by 1345
Abstract
Background: Histamine H2 receptor antagonists are a group of drugs that inhibit gastric juice secretion in gastrointestinal diseases. However, there is evidence to suggest that H2 blockers have a broader spectrum of activity. The antioxidant properties of H2 blockers have not been fully [...] Read more.
Background: Histamine H2 receptor antagonists are a group of drugs that inhibit gastric juice secretion in gastrointestinal diseases. However, there is evidence to suggest that H2 blockers have a broader spectrum of activity. The antioxidant properties of H2 blockers have not been fully elucidated, and their anti-glycation potential has not been studied to date. Therefore, this is the first study to compare the antioxidant and antiglycation potentials of the most popular H2 antagonists (ranitidine, cimetidine, and famotidine) on protein glycoxidation in vitro. Methods: Bovine serum albumin (BSA) was glycated using sugars (glucose, fructose, galactose, and ribose) as well as aldehydes (glyoxal and methylglyoxal). Results: In the analyzed group of drugs, ranitidine was the only H2 blocker that significantly inhibited BSA glycation in all tested models. The contents of protein carbonyls, protein glycoxidation products (↓dityrosine, ↓N-formylkynurenine), and early (↓Amadori products) and late-stage (↓AGEs) protein glycation products decreased in samples of glycated BSA with the addition of ranitidine relative to BSA with the addition of the glycating agents. The anti-glycation potential of ranitidine was comparable to those of aminoguanidine and Trolox. In the molecular docking analysis, ranitidine was characterized by the lowest binding energy for BSA sites and could compete with protein amino groups for the addition of carbonyl groups. H2 blockers also scavenge free radicals. The strongest antioxidant properties are found in ranitidine, which additionally has the ability to bind transition metal ions. The systematic literature review also revealed that the anti-glycation effects of ranitidine could be attributed to its antioxidant properties. Conclusions: Ranitidine showed anti-glycation and antioxidant properties. Further research is needed, particularly in patients with diseases that promote protein glycation. Full article
(This article belongs to the Special Issue Histamine Receptor Ligands in Medicinal Chemistry)
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20 pages, 5833 KiB  
Article
Guanidines: Synthesis of Novel Histamine H3R Antagonists with Additional Breast Anticancer Activity and Cholinesterases Inhibitory Effect
by Marek Staszewski, Magdalena Iwan, Tobias Werner, Marek Bajda, Justyna Godyń, Gniewomir Latacz, Agnieszka Korga-Plewko, Joanna Kubik, Natalia Szałaj, Holger Stark, Barbara Malawska, Anna Więckowska and Krzysztof Walczyński
Pharmaceuticals 2023, 16(5), 675; https://doi.org/10.3390/ph16050675 - 30 Apr 2023
Cited by 2 | Viewed by 2105
Abstract
This study examines the properties of novel guanidines, designed and synthesized as histamine H3R antagonists/inverse agonists with additional pharmacological targets. We evaluated their potential against two targets viz., inhibition of MDA-MB-231, and MCF-7 breast cancer cells viability and inhibition of AChE/BuChE. [...] Read more.
This study examines the properties of novel guanidines, designed and synthesized as histamine H3R antagonists/inverse agonists with additional pharmacological targets. We evaluated their potential against two targets viz., inhibition of MDA-MB-231, and MCF-7 breast cancer cells viability and inhibition of AChE/BuChE. ADS10310 showed micromolar cytotoxicity against breast cancer cells, combined with nanomolar affinity at hH3R, and may represent a promising target for the development of an alternative method of cancer therapy. Some of the newly synthesized compounds showed moderate inhibition of BuChE in the single-digit micromolar concentration ranges. H3R antagonist with additional AChE/BuChE inhibitory effect might improve cognitive functions in Alzheimer’s disease. For ADS10310, several in vitro ADME-Tox parameters were evaluated and indicated that it is a metabolically stable compound with weak hepatotoxic activity and can be accepted for further studies. Full article
(This article belongs to the Special Issue Histamine Receptor Ligands in Medicinal Chemistry)
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Review

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40 pages, 1147 KiB  
Review
Function and Role of Histamine H1 Receptor in the Mammalian Heart
by Joachim Neumann, Britt Hofmann, Uwe Kirchhefer, Stefan Dhein and Ulrich Gergs
Pharmaceuticals 2023, 16(5), 734; https://doi.org/10.3390/ph16050734 - 11 May 2023
Cited by 2 | Viewed by 5728
Abstract
Histamine can change the force of cardiac contraction and alter the beating rate in mammals, including humans. However, striking species and regional differences have been observed. Depending on the species and the cardiac region (atrium versus ventricle) studied, the contractile, chronotropic, dromotropic, and [...] Read more.
Histamine can change the force of cardiac contraction and alter the beating rate in mammals, including humans. However, striking species and regional differences have been observed. Depending on the species and the cardiac region (atrium versus ventricle) studied, the contractile, chronotropic, dromotropic, and bathmotropic effects of histamine vary. Histamine is present and is produced in the mammalian heart. Thus, histamine may exert autocrine or paracrine effects in the mammalian heart. Histamine uses at least four heptahelical receptors: H1, H2, H3 and H4. Depending on the species and region studied, cardiomyocytes express only histamine H1 or only histamine H2 receptors or both. These receptors are not necessarily functional concerning contractility. We have considerable knowledge of the cardiac expression and function of histamine H2 receptors. In contrast, we have a poor understanding of the cardiac role of the histamine H1 receptor. Therefore, we address the structure, signal transduction, and expressional regulation of the histamine H1 receptor with an eye on its cardiac role. We point out signal transduction and the role of the histamine H1 receptor in various animal species. This review aims to identify gaps in our knowledge of cardiac histamine H1 receptors. We highlight where the published research shows disagreements and requires a new approach. Moreover, we show that diseases alter the expression and functional effects of histamine H1 receptors in the heart. We found that antidepressive drugs and neuroleptic drugs might act as antagonists of cardiac histamine H1 receptors, and believe that histamine H1 receptors in the heart might be attractive targets for drug therapy. The authors believe that a better understanding of the role of histamine H1 receptors in the human heart might be clinically relevant for improving drug therapy. Full article
(This article belongs to the Special Issue Histamine Receptor Ligands in Medicinal Chemistry)
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