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- Title
Pharmacological and SAR analysis of the LINS01 compounds at the human histamine H<sub>1</sub>, H<sub>2</sub>, and H<sub>3</sub> receptors.
- Authors
Corrêa, Michelle Fidelis; Barbosa, Álefe Jhonatas Ramos; Fernandes, Gustavo Ariel Borges; Fernandes, João Paulo dos Santos; Baker, Jillian G.
- Abstract
Histamine is a transmitter that activates the four receptors H1R to H4R. The H3R is found in the nervous system as an autoreceptor 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 the selectivity for the H3R over the H4R. Here, we describe their pharmacological properties at the human H1R and 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 was 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 while the N‐phenyl group is detrimental. The methoxy derivative, LINS01009, had the highest affinity. LINS01 compounds have been evaluated as H3R/H4R antagonists, showing very promising anti‐inflammatory activity in murine asthma model. The paper examines their pharmacological properties at the human H1R, H2R, and H3R in parallel, thus completing the pharmacological analysis across all the histamine receptors.
- Subjects
HISTAMINE receptors; ANTIHISTAMINES; LIGANDS (Biochemistry); STRUCTURE-activity relationships; METHOXY group
- Publication
Chemical Biology & Drug Design, 2019, Vol 93, Issue 1, p89
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.13387