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Histamine Receptor Ligands in Medicinal Chemistry

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

Deadline for manuscript submissions: closed (25 April 2024) | Viewed by 8951

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Special Issue Editors

Prof. Dr. Krzysztof Walczyński

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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

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Guest Editor

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

Published Papers (4 papers)

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Research

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12 pages, 3522 KiB

Open AccessArticle

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 498

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 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

Open AccessArticle

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 - 08 Sep 2023

Cited by 2 | Viewed by 1033

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 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

Open AccessArticle

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 1 | Viewed by 1854

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. 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

Open AccessReview

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 4788

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 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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