Pharmacological and SAR analysis of the LINS01 compounds at the human histamine H1, H2 and H3 receptors

Corrêa, Michelle Fidelis; Barbosa, Álefe Jhonatas Ramos; Fernandes, Gustavo Ariel Borges; Baker, Jillian G.; dos Santos Fernandes, João Paulo

Abstract

Histamine is a transmitter that activates the four receptors H1R to H4R. The H3R is found in the nervous system as an auto and heteroreceptor, and controls the release of neurotransmitters, making it a potential drug target for neuropsychiatric conditions. We have previously reported that the 1‐(2,3‐dihydro‐1‐benzofuran‐2‐yl)methylpiperazines (LINS01 compounds) have selectivity for the H3R over the H4R. Here we describe their pharmacological properties at the human H1R, H2R in parallel with the H3R, thus providing a full analysis of these compounds as histamine receptor ligands through reporter gene assays. Eight of the nine LINS01 compounds inhibited H3R‐induced histamine responses but no inhibition of H2R‐induced responses were seen. Three compounds were weakly able to inhibit H1R‐induced responses. No agonist responses were seen to any of the compounds at any receptor. SAR analysis shows that the N‐methyl group improves H3R affinity whilst the N‐phenyl group is detrimental. The methoxy derivative, LINS01009, had the highest affinity.

Citation

Corrêa, M. F., Barbosa, Á. J. R., Fernandes, G. A. B., Baker, J. G., & dos Santos Fernandes, J. P. (2018). Pharmacological and SAR analysis of the LINS01 compounds at the human histamine H1, H2 and H3 receptors. Chemical Biology and Drug Design, 93(1), 89-95. https://doi.org/10.1111/cbdd.13387

• Journal Article Type: Article
• Acceptance Date: Aug 17, 2018
• Online Publication Date: Aug 28, 2018
• Publication Date: Aug 28, 2018
• Deposit Date: Sep 7, 2018
• Publicly Available Date: Aug 29, 2019
• Journal: Chemical Biology & Drug Design
• Print ISSN: 1747-0277
• Electronic ISSN: 1747-0285
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 93
• Issue: 1
• Pages: 89-95
• DOI: https://doi.org/10.1111/cbdd.13387
• Keywords: Antihistamines; Histamine receptor ligands; H3R antagonists; Ligand efficiency analysis; Structure-activity relationships
• Public URL: https://nottingham-repository.worktribe.com/output/1065311
• Publisher URL: https://onlinelibrary.wiley.com/doi/abs/10.1111/cbdd.13387
• Additional Information: This is the peer reviewed version of the following article: Corrêa, M. F., Barbosa, Á. J., Fernandes, G. A., Baker, J. G. and dos Santos Fernandes, J. P. (2018), Pharmacological and SAR analysis of the LINS01 compounds at the human histamine H1, H2 and H3 receptors. Chem Biol Drug Des. 10.1111/cbdd.13387, which has been published in final form at https://onlinelibrary.wiley.com/doi/abs/10.1111/cbdd.13387. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
• Contract Date: Sep 7, 2018