4-Methylhistamine dihydrochloride

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Background

4-Methylhistamine dihydrochloride (or 4-methylhistamine) is a selective agonist of H4 receptor with a pEC50 value of 7.4±0.1 (α=1) [1].
In the chemotaxis of mast cells and leukocytes to sites of inflammation, the histamine H4 receptor (H4R) is involved [1].
In transfected cells, 4-methylhistamine bound to hH4R with the highest affinity, compared to the binding to other histamine receptors. The interaction between 4-methylhistamine and hH4R showed a higher selectivity than that between the drug and the H3R and H2R, and H1R by >100-fold and >100,000-fold, respectively. 4-Methylhistamine also had a high affinity for the rat and mouse H4R with Ki values of 73 and 55 nM, respectively, though this affinity was lower than that for hH4R. The agonistic effects of 4-methylhistamine to hH4R were antagonized by JNJ 7777120, a selective H4R antagonist. To the rat and mouse H4R, as a full H4 agonist, 4-methylhistamine showed pEC50 values of 5.6 ± 0.1 and 5.8 ± 0.1, respectively [1].
After being fasted for 18 h, rats were administered intraperitoneally (i.p.) with a single dose of 4-methylhistamine. 2 h later, they were subjected to a intra-articular (i.a.) injection of LPS. In both groups treated with 4-methylhistamine and LPS alone, respectively, the expression of TNF-α and NF-κB was increased, levels of IkB-α were decreased in synovial fluid and whole blood. Further, mRNA levels of IL-1β, TNF-α, and NF-κB were significantly increased. Western blot analysis results also confirmed that the expression of TNF-α, JAK-1, NF-κB and STAT-3 was increased in both 4-methylhistamine and LPS treatment groups. In the inflamed knee tissue of the JNJ 7777120-treated group, these increases were completely inhibited [2].

[1]. Lim HD, van Rijn RM, Ling P, et al. Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist. Journal of Pharmacology and Experimental Therapeutics, 2005, 314(3): 1310-1321.
[2]. Ahmad SF, Ansari MA, Zoheir KMA, et al. Regulation of TNF-α and NF-κB activation through the JAK/STAT signaling pathway downstream of histamine 4 receptor in a rat model of LPS-induced joint inflammation. Immunobiology, 2015, 220(7): 889-898.