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  • In conclusion the most salient

    2022-08-08

    In conclusion, the most salient observation from this study was that PAE reduced the expression of HDC protein expression in dentate gyrus, cerebral cortex, and cerebellum, but not in the caudate nucleus or ventral hypothalamus. The regional basis for this heightened sensitivity is not known, but it is generally consistent with other studies reporting greater sensitivity of these regions to the effects of even moderate PAE. One intriguing notion relates to the fact that the three LY2606368 regions where moderate PAE reduced HDC expression (Fig. 4) were also brain regions where PAE elevated histamine H3 receptor-effector coupling (Varaschin et al., 2018). By contrast, neither HDC expression (Fig. 4) nor H3 receptor-effector coupling (Varaschin et al., 2018) were diminished in the dorso-medial caudate nucleus of PAE rat offspring. Whether a causal relationship exists between reduced levels of HDC and elevated H3 receptor-effector coupling is unknown. One possible line of speculation is that a diminished presynaptic histaminergic influence, as reflected in reduced HDC levels, may have led to a compensatory increase in histamine H3 receptor-mediated responses on nearby nerve terminals. However, this line of reasoning is not consistent with the effects of PAE on the histamine H2 receptor system residing on different postsynaptic targets within the dentate gyrus. Future studies employing brain-region specific siRNA knockdown of HDC expression could address the relationship between HDC and H3 receptor function.
    Declaration of interest
    Acknowledgments The authors wish to thank Ms. Denise Cordaro, Mr. Nathan Boyer, Ms. Christie Wilcox, and Dr. Kevin O'Hair for their outstanding animal care support for this project. This work was supported by NIHNIAAA1 P20 AA017068, 1 RO1 AA019884 and 1 P50 AA022534.
    Histamine (, ), one of the neurotransmitters, functions through four different histamine receptor subtypes in the whole body. These receptor subtypes, which belong to seven-transmembrane G protein-coupled receptors (GPCRs), are classified into H, H, H, and H receptors. Among them, the H receptor (HR) cloned in early the 2000s is mainly expressed in various immune system cells such as eosinophils, dendritic cells, mast cells, and leukocytes. The HR is also involved in cutaneous tissues and central nervous system. Since indole- or benzimidazole-piperazine derivatives, JNJ7777120 () and JNJ10191584 () shown in , were identified as the first non-imidazole HR selective antagonists through high-throughput screening, various physiological functions of the HR have been elucidated, and the HR has been expected as a therapeutic target for autoimmune and inflammatory diseases. In fact, for example, an HR selective antagonist, JNJ38518168 (), advanced to Phase II in the clinical trial as a remedy for asthma and rheumatoid arthritis. Additionally, HR antagonists have shown synergistic effects with H receptor (HR) antagonists in the treatment of allergic diseases including atopic dermatitis. Thus, HR selective antagonists can be high potential therapeutic candidates, although there are no ligands as approved medicines yet. In design of bioactive molecules, three-dimensional LY2606368 structure information of the target protein is significantly beneficial. However, the X-ray crystal structure analysis of the HR has not succeeded. Although there are various reports of homology modeling of the HR based on the crystal structure of the bovine rhodopsin, the adrenergic GPCR, or the HR, the estimated binding modes of histamine and HR ligands are somewhat different depending on the models. Therefore, the precise binding modes are still unclear. To efficiently develop bioactive ligands even if the structural information of the target protein is unknown, we have presented a three-dimensional structural diversity-oriented strategy based on structural properties of a chiral cyclopropane. Our strategy has allowed us to design and synthesize a series of cyclopropane-based conformationally restricted histamine analogues having imidazolylcyclopropane scaffold. Through the studies, we successfully identified a selective and potent antagonist for the H receptor (HR) (H,  = 5.3 nM; H,  = 127 nM) and a non-selective potent antagonist for the HR and the HR (H,  = 8.4 nM; H,  = 7.6 nM) shown in . However, as for HR selectivity, even the most potent HR-selective compound in the series of the imidazolylcyclopropane derivatives, the selectivity and potency were moderate (H,  > 1,000 nM; H,  = 118 nM). Thus, in this study, we aimed to convert the potent H/H dual antagonist and the moderate HR-selective antagonist into a highly HR-selective ligand. The indole/benzimidazole-piperazine derivatives have two nitrogen-containing ring moieties, an indole/benzimidazole () and piperazine (), in their structures (). We thought that these moieties, or , might make the molecules highly HR-selective. The imidazolylcyclopropane derivatives also have two nitrogen-containing moieties, an imidazole () and benzylamine (), which correspond to the or . Thus, we have designed cyclopropane derivatives – as H selective antagonists, which have the or moiety instead of the or in the imidazolylcyclopropane derivatives (). This molecular design might improve the HR selectivity of cyclopropane-based derivatives to give an insight into the binding modes of the cyclopropane-based compounds and the indole/benzimidazole-piperazine derivatives to the HR.