**Background**
Allergic diseases are characterized by hypersensitivity reactions involving the release of proinflammatory mediators from mast cells, basophils, and eosinophils. The H1-histamine receptor plays a central role in mediating the immediate symptoms of allergy, while the P2X7 receptor, an ATP-gated ion channel, is heavily involved in the activation of the NLRP3 inflammasome and the subsequent release of proinflammatory cytokines. Targeting these pathways simultaneously offers a potent strategy for reducing inflammation and alleviating allergic symptoms. In this context, we will introduce a dual antagonist of the H1-histamine receptor and the P2X7 receptor – Oxatomide.
**Definition**
Oxatomide is an orally active dual antagonist of the H1-histamine receptor and the P2X7 receptor, as well as an inhibitor of serotonin, which possesses antihistaminic, antiallergic, and anti-inflammatory activities.
**In Vitro and In Vivo Studies**
According to the Oxatomide technical information, this compound demonstrates significant inhibitory effects across various cellular models. In Oxatomide in vitro studies, Oxatomide (1-30 μM; 0-60 s) inhibited the elevation of [Ca2+]i induced by 1 mM ATP in N18TG2 cells with an IC50 of 3.37 μM. Furthermore, pre-treatment with Oxatomide (10 μM) inhibited the phosphorylation of ERK and p38 MAPK induced by ATP in N18TG2 cells, as well as the upregulation of COX-2 and MIP-2 mRNA and the secretion of MIP-2 induced by BzATP in J774 macrophages. In human basophils, Oxatomide (0.1-10 μM; 15 min) inhibited the immunological release of histamine and LTC4. Similarly, in human skin mast cells, it inhibited the release of histamine, tryptase, and PGD2 following stimulation by anti-IgE or anti-FcεRI. Additionally, Oxatomide (0-30 μM; 0-48 h) was found to promote the apoptosis of peripheral blood eosinophils and inhibit their survival induced by IL-5.
Regarding Oxatomide in vivo activity, the compound was evaluated in a chinchilla model of immune-mediated exudative otitis media. Administration via oral gavage (5-30 mg/kg; 5 days to 2 weeks) showed that doses of 10 and 30 mg/kg alleviated experimental otitis media with effusion. Specifically, the 30 mg/kg dose significantly reduced the mean LTD4 concentration in middle ear effusion, demonstrating that the drug is rapidly absorbed and transported to the middle ear. In conclusion, Oxatomide is a potent dual H1 and P2X7 receptor antagonist that holds promise for the research of allergic and inflammatory diseases.
Keywords
Oxatomide, 60607-34-3, KW-4354, KW4354, KW 4354, Histamine Receptor, P2X Receptor, 5-HT Receptor, Apoptosis, PERK, p38 MAPK, COX, P2XRs, Serotonin Receptor, 5-hydroxytryptamine Receptor
References
[1] Kazuki Yoshida, et al. P2X7 receptor antagonist activity of the anti-allergic agent oxatomide. Eur J Pharmacol. 2015 Nov 15;767:41-51.
[2] Tanaka T,et al. Effect of oxatomide on otitis media with effusion–an experimental study. Acta Otolaryngol. 1995 Jul;115(4):532-8.
[3] Domae M, et al. The antiallergic drug oxatomide promotes human eosinophil apoptosis and suppresses IL-5-induced eosinophil survival. J Allergy Clin Immunol. 2003 Mar;111(3):567-72.
[4] Patella V, et al. Oxatomide inhibits the release of proinflammatory mediators from human basophils and mast cells. Int Arch Allergy Immunol. 1996 Sep;111(1):23-9.