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  • Furthermore Rosethorne and Charlton Panula et

    2021-09-15

    Furthermore, Rosethorne and Charlton (Panula et al., 2015, Reher et al., 2012, Rosethorne and Charlton, 2011) expressed the human H4R in an osteosarcoma cell line and found that with respect to [35S]GTPγS binding, JNJ-7777120 acted as a neutral antagonist or very weak inverse agonist, a finding which makes matters more complicated. In obvious contrast, with respect to translocation of β-arrestin to the synthase membrane, JNJ-7777120 showed strong partial agonistic activity. Additionally, JNJ-7777120 prompted a delayed activation of the mitogen-activated protein kinase pathway which is characteristic for β-arrestin-mediated signal transduction (Luttrell and Gesty-Palmer, 2010, Panula et al., 2015). On the other hand, the described biased H4R receptor signaling by JNJ-7777120 has in the meantime been protracted to a wider range of benzimidazole analogs (Nijmeijer et al., 2012, Nijmeijer et al., 2013, Panula et al., 2015), but testing a variety of known H4R ligands has resulted in the identification of biased ligands for both the G-protein and β-arrestin pathways. The aforementioned findings point to the possible complex pharmacology of the H4R and JNJ-7777120, despite the fact that such data are presently constrained to transfected cell systems and have not been observed in primary cells. Notably and in order to assess whether H4Rs will be successfully antagonized in the clinic, an interesting biomarker has been developed by which H4R antagonists capable of inhibiting eosinophil shape change induced by imetit (31, H4R agonist) can be monitored by the eosinophil Gated Autofluorescence Forward Scatter (GAFS) assay. This inhibition of imetit-induced GAFS response in whole blood is a validated biomarker of H4R antagonism (Barnard et al., 2008, Buckland et al., 2003, Ling et al., 2004, Mowbray et al., 2011, Thurmond et al., 2014). Likewise, some biased ligands have, also, been identified and described for the H2R (Alonso et al., 2014). Differences were also described in vivo and in primary cells. In a murine model of allergic asthma, the effects of the H4R antagonist JNJ-7777120 (52), the H3R antagonist JNJ-5207852 (41) and the H3R and H4R antagonist thioperamide (35) were compared when given during the sensitization phase in ovalbumin-induced allergic asthma (Neumann et al., 2013). After provocation, JNJ-7777120 resulted in reduced serum titers of ovalbumin-specific IgE, inflammatory infiltrations in the lungs and eosinophils in the bronchoalveolar lavage as earlier reported (Dunford et al., 2006). Thioperamide (35) did not completely mimic the results seen with JNJ-7777120 as it only resulted in lower eosinophil counts in the bronchoalveolar lavage, Noticeably, JNJ-5207852 had no effect on the studied parameters (Panula et al., 2015). The apparent detach between the results observed with JNJ-7777120 and thioperamide led to some speculations that JNJ-7777120 could have effects other than blocking the H4R. Nonetheless, these discrepancies can also be explained by the known low selectivity profile of thioperamide (such as dual H3R/H4R antagonism) or differences in pharmacokinetics. In monocytes as native human cells, a study compared the ability of different H4R agonists (4(5)-methylhistamine (16), UR-PI376 (61), clobenpropit (36), VUF8430 (50) and ST-1006 (51) in their ability to suppress IFNα+LPS induced IL-12 production (Gschwandtner et al., 2013). All tested agonists had substantially lower potencies in this assay as compared to published data from transfected cell lines, and the effect could be only partly blocked by JNJ-7777120 in the case of 4(5)-methylhistamine, UR-PI376, clobenpropit and VUF8430 but completely blocked the ST-1006 effect. Lastly, a study related the development of murine autoimmune encephalomyelitis in histidine-decarboxylase knockout mice lacking histamine to knockout mice lacking all four known histamine receptors (Saligrama et al., 2013). The findings revealed that many of the symptoms were relieved in H1R–H4R knockout mice, while the encephalomyelitis was aggravated in histidine-decarboxylase knockout mice. One of the speculations raised by the authors was that there might be histamine signaling pathways independent from the known H1R–H4R.