4-Methylhistamine dihydrochloride

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].

References:
[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.

Regulation of TNF-alpha and NF-kappaB activation through the JAK/STAT signaling pathway downstream of histamine 4 receptor in a rat model of LPS-induced joint inflammation.[Pubmed:25666529]

Immunobiology. 2015 Jul;220(7):889-98.

Histamine 4 receptor (H4R) is a novel target for the pharmacological modulation of histamine-mediated immune signals during inflammatory diseases. The purpose of this study was to assess the effects of the H4R agonist 4-Methylhistamine dihydrochloride (4-MeH) and antagonist JNJ7777120 (JNJ) in the inflamed rat knee. Animals were fasted for 18h before a single dose of 4-MeH or JNJ (30mg/kg) was administered intraperitoneally (i.p.), both followed by intra-articular (i.a.) injection of LPS 2h later. Blood and synovial fluid were collected after a short incubation period and TNF-alpha, NF-kappaB, and IkB-alpha levels were measured via flow cytometry. Additionally, we assessed the effects of H4R engagement on the expression of IL-1beta, TNF-alpha, and NF-kappaB mRNAs and the protein levels of TNF-alpha, NF-kappaB, JAK-1, and STAT-3 in the inflamed knee tissue. These results revealed increased TNF-alpha and NF-kappaB expression and decreased IkB-alpha levels in both the LPS alone and 4-MeH treated groups in whole blood and synovial fluid. Further, IL-1beta, TNF-alpha, and NF-kappaB mRNA levels were significantly increased and western blot analysis confirmed increased expression of TNF-alpha, NF-kappaB, JAK-1, and STAT-3 in both LPS and 4-MeH treatment groups. Furthermore, these increases were completely inhibited in the inflamed knee tissue of the JNJ-treated group. Thus, the inhibition of inflammatory mediators and signaling pathways by the H4R antagonist JNJ suggests the anti-arthritic importance of this molecule.

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.[Pubmed:15947036]

J Pharmacol Exp Ther. 2005 Sep;314(3):1310-21.

The histamine H(4) receptor (H(4)R) is involved in the chemotaxis of leukocytes and mast cells to sites of inflammation and is suggested to be a potential drug target for asthma and allergy. So far, selective H(4)R agonists have not been identified. In the present study, we therefore evaluated the human H(4)R (hH(4)R) for its interaction with various known histaminergic ligands. Almost all of the tested H(1)R and H(2)R antagonists, including several important therapeutics, displaced less than 30% of specific [(3)H]histamine binding to the hH(4)R at concentrations up to 10 microM. Most of the tested H(2)R agonists and imidazole-based H(3)R ligands show micromolar-to-nanomolar range hH(4)R affinity, and these ligands exert different intrinsic hH(4)R activities, ranging from full agonists to inverse agonists. Interestingly, we identified 4-methylhistamine as a high-affinity H(4)R ligand (K(i) = 50 nM) that has a >100-fold selectivity for the hH(4)R over the other histamine receptor subtypes. Moreover, 4-methylhistamine potently activated the hH(4)R (pEC(50) = 7.4 +/- 0.1; alpha = 1), and this response was competitively antagonized by the selective H(4)R antagonist JNJ 7777120 [1-[(5-chloro-1H-indol-2-yl)-carbonyl]-4-methylpiperazine] (pA(2) = 7.8). The identification of 4-methylhistamine as a potent H(4)R agonist is of major importance for future studies to unravel the physiological roles of the H(4)R.