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Cognitive Functions, Attention-Deficit Hyperactivity Disorders, and Alzheimer’s Disease
Published in Divya Vohora, The Third Histamine Receptor, 2008
Maria Beatrice Passani, Patrizio Blandina, Kaitlin E. Browman, Gerard B. Fox
From the early 1980s, histamine H3 receptor antagonists containing an imidazole moiety, such as ciproxifan, thioperamide, and clobenpropit, were developed and subsequently evaluated across a range of behavioral tests in various rodent strains, including the SHR. These compounds were efficacious across a number of different cognitive domains, including attention. Although these first-generation drugs served as early reference standards, imidazole-ring containing ligands are not suitable compounds to develop as drugs in humans since they are associated with inhibition of cytochrome P450 enzymes, potentially leading to drug–drug interactions. In addition, the affinity of some compounds such as thioperamide for the human H3 receptor is low when compared to the rodent receptor [62,63]. However, the successful cloning and functional expression of the histamine H3 receptors from various species over the past 10 years [64] has greatly facilitated efforts to identify nonimidazole-based small molecule antagonists. Investigators at Abbott Laboratories have demonstrated improved cognitive performance in the 5-TIA model in SHRs following administration of potent and selective antagonists such as ABT-239 [65] and other nonimidazole- [36,65–67] and imidazole-based [36,66] H3 receptor antagonists. Investigators at Johnson & Johnson have also shown significant improvements in a 7-TIA variant of this model of ADHD in SHRs with the nonimidazole H3 antagonist, JNJ-180181457 [68].
Activation of carbonic anhydrase isoforms involved in modulation of emotional memory and cognitive disorders with histamine agonists, antagonists and derivatives
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Gustavo Provensi, Alessio Nocentini, Maria Beatrice Passani, Patrizio Blandina, Claudiu T. Supuran
Some of these compounds, possessing structures 2–30 (Figure 1), were included in our study for investigating their possible CA activating effects against four pharmacologically relevant human isoforms, hCA I, II, IV and VII. The compounds were numbered according to their similarity to the lead histamine 1 and are: the H1R agonist 2-(2-aminoethyl)thiazole 6; the H2R agonists impromidine 16 and nordimaprit 19; the H3R agonists Nπ-methylhistamine 3, α-methylhistamine 4, methimmepip 8, proxyfan 9, imetit 14, VUF16839 23; the H1R antagonists pyrilamine 24, loratadine 29; the H2R antagonists metiamide 12, cimetidine 13, ranitidine 17, tiotidine 18, zolantidine 20; the H3R antagonists ciproxifan 10, clobenpropit 15, ABT239 22, GSK189254A 28, GSK334429B 30; the H4R antagonists JNJ39758979 25, JNJ7777120 26, A940894 27; the mixed modulators of the histaminergic system Nτ-methylhistamine 2, 4-methylhistamine 5, 1-methylhistidine 7, burimamide 11, betahistine 21.
Design, synthesis, and anticonvulsant effects evaluation of nonimidazole histamine H3 receptor antagonists/inverse agonists containing triazole moiety
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Mingxia Song, Rui Yan, Yanhui Zhang, Dongfu Guo, Naiming Zhou, XianQing Deng
cAMP-response element (CRE) reporter gene assay has been extensively used to evaluate the efficacy of GPCR antagonists or agonists. In this work, the H3R antagonistic activities of the prepared 3-(4-(4H-1,2,4-triazol-4-yl)phenoxy)-propylamine derivatives have been screened by CRE-driven luciferase assay, in which the HEK-293 cells expressing the human H3R and a reporter gene consisting of the firefly luciferase coding region were used43,44. Ciproxifan (CXP) and Pitolisant (PIT) were employed as the positive controls. Initially, compounds and positive controls were tested at two concentrations (100 nM and 1 µM) to obtain the preliminary investigation of their H3R antagonistic activities. In the assays, the antagonistic activities was positively correlated with the rise of the fluorescence value and indicated by the % antagonism. For the prominent compounds IC50 values were determined at additional assays.
Differential expression and signaling of the human histamine H3 receptor isoforms of 445 and 365 amino acids expressed in human neuroblastoma SH-SY5Y cells
Published in Journal of Receptors and Signal Transduction, 2018
Gustavo Nieto-Alamilla, Juan Escamilla-Sánchez, María-Cristina López-Méndez, Anayansi Molina-Hernández, Agustín Guerrero-Hernández, José-Antonio Arias-Montaño
Regarding the affinity for selective ligands, in transfected C6 cells agonists exhibited a higher affinity for the hH3R365 isoform, whereas antagonists/inverse agonists displayed the opposite preference [9]. In our experiments, both hH3R isoforms showed similar affinity for the labeled agonist [3 H]-NMHA, for the agonists histamine, immepip and RAMH, and for the antagonist/inverse agonists A-331440, ciproxifan and clobenpropit. These results agree with data reported by Cogé et al. [7] and our own data for the isoforms expressed in CHO-K1 cells [19]. Taken together, differences in receptor expression and affinity appear to depend on both the cell type in which isoforms are expressed, and the radioligand employed to label H3Rs.