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Pharmacological and SAR analysis of the LINS 01 compounds at the human histamine H 1 , H 2 , and H 3 receptors
Author(s) -
Corrêa Michelle Fidelis,
Barbosa Álefe Jhonatas Ramos,
Fernandes Gustavo Ariel Borges,
Baker Jillian G.,
Fernandes João Paulo dos Santos
Publication year - 2019
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13387
Subject(s) - histamine , chemistry , receptor , histamine h3 receptor , agonist , autoreceptor , histamine receptor , histamine h4 receptor , stereochemistry , biochemistry , pharmacology , histamine h2 receptor , biology , antagonist
Abstract Histamine is a transmitter that activates the four receptors H 1 R to H 4 R. The H 3 R 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 ( LINS 01 compounds) have the selectivity for the H 3 R over the H 4 R. Here, we describe their pharmacological properties at the human H 1 R and H 2 R in parallel with the H 3 R, thus providing a full analysis of these compounds as histamine receptor ligands through reporter gene assays. Eight of the nine LINS 01 compounds inhibited H 3 R‐induced histamine responses, but no inhibition of H 2 R‐induced responses was seen. Three compounds were weakly able to inhibit H 1 R‐induced responses. No agonist responses were seen to any of the compounds at any receptor. SAR analysis shows that the N ‐methyl group improves H 3 R affinity while the N ‐phenyl group is detrimental. The methoxy derivative, LINS 01009, had the highest affinity.