دورية أكاديمية
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Pharmacological characterization of seven human histamine H 3 receptor isoforms.

التفاصيل البيبلوغرافية
العنوان: Pharmacological characterization of seven human histamine H 3 receptor isoforms.
المؤلفون: Gao M; Department of Medicinal Chemistry, Amsterdam Institute of Molecular Life Sciences, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, the Netherlands., Dekker ME; Department of Medicinal Chemistry, Amsterdam Institute of Molecular Life Sciences, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, the Netherlands., Leurs R; Department of Medicinal Chemistry, Amsterdam Institute of Molecular Life Sciences, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, the Netherlands. Electronic address: r.leurs@vu.nl., Vischer HF; Department of Medicinal Chemistry, Amsterdam Institute of Molecular Life Sciences, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, the Netherlands. Electronic address: h.f.vischer@vu.nl.
المصدر: European journal of pharmacology [Eur J Pharmacol] 2024 Apr 05; Vol. 968, pp. 176450. Date of Electronic Publication: 2024 Feb 21.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 1254354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0712 (Electronic) Linking ISSN: 00142999 NLM ISO Abbreviation: Eur J Pharmacol Subsets: MEDLINE
أسماء مطبوعة: Publication: 2005- : Amsterdam : Elsevier Science
Original Publication: Amsterdam, North Holland Pub. Co.
مواضيع طبية MeSH: Histamine*/pharmacology , Receptors, Histamine H3*/metabolism, Humans ; Drug Inverse Agonism ; Receptors, Histamine ; Protein Isoforms ; Histamine Agonists/pharmacology
مستخلص: The histamine H 3 receptor (H 3 R) regulates as a presynaptic G protein-coupled receptor the release of histamine and other neurotransmitters in the brain, and is consequently a potential therapeutic target for neuronal disorders. The human H 3 R encodes for seven splice variants that vary in the length of intracellular loop 3 and/or the C-terminal tail but are all able to induce heterotrimeric G i protein signaling. The last two decades H 3 R drug discovery and lead optimization has been exclusively focused on the 445 amino acids-long reference isoform H 3 R-445. In this study, we pharmacologically characterized for the first time all seven H 3 R isoforms by determining their binding affinities for reference histamine H 3 receptor agonists and inverse agonists. The H 3 R-453, H 3 R-415, and H 3 R-413 isoforms display similar binding affinities for all ligands as the H 3 R-445. However, increased agonist binding affinities were observed for the three shorter isoforms H 3 R-329, H 3 R-365, and H 3 R-373, whereas inverse agonists such as the approved anti-narcolepsy drug pitolisant (Wakix®) displayed significantly decreased binding affinities for the latter two isoforms. This opposite change in binding affinity of agonist versus inverse agonists on H 3 R-365 and H 3 R-373 is associated with their higher constitutive activity in a cAMP biosensor assay as compared to the other five isoforms. The observed differences in pharmacology between longer and shorter H 3 R isoforms should be considered in future drug discovery programs.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Meichun Gao reports financial support was provided by CSC Chinese scholarship grant. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
فهرسة مساهمة: Keywords: Binding selectivity; Constitutive activity; Efficacy; GPCR; Histamine H(3) receptor; Isoforms
المشرفين على المادة: 820484N8I3 (Histamine)
0 (Receptors, Histamine H3)
0 (Receptors, Histamine)
0 (Protein Isoforms)
0 (Histamine Agonists)
تواريخ الأحداث: Date Created: 20240222 Date Completed: 20240311 Latest Revision: 20240311
رمز التحديث: 20240311
DOI: 10.1016/j.ejphar.2024.176450
PMID: 38387718
قاعدة البيانات: MEDLINE
الوصف
تدمد:1879-0712
DOI:10.1016/j.ejphar.2024.176450