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Drug Discovery: From Hits to Clinical Candidates
Published in Divya Vohora, The Third Histamine Receptor, 2008
Sylvain Celanire, Florence Lebon, Holger Stark
The pharmacophore model was validated through the synthesis of a novel series of clobenpropit-based antagonists with high H3R affinity, designed to interact with all four hydrogen-bonding sites and the two hydrophobic pockets as exemplified by VUF5228 (182) (Figure 5.28). Branched compounds (e.g., 183), published from the Schering research group, further supported this pharmacophore model (Figure 5.25) [220].
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
Early, anticonvulsant activity of some imidazole H3R antagonists such as thioperamide and clobenpropit was confirmed in models of epilepsy (Figure 1)16,19,20,23. Recently, a large number of non-imidazole H3R antagonists such as DL77 (Figure 1) prepared by a group/team of Kiec-Kononowicz exhibited excellent anticonvulsant activity in the electrically-induced seizures model and subcutaneously pentylenetetrazole (PTZ)-induced seizure model at dose-dependent, and the therapeutic action was proved through H3R24–28. Sadek et al. synthesised some histamine H3R ligands (Figure 1, I) incorporating different antiepileptic structural motifs to investigate if the H3R pharmacophore could be combined to some antiepileptic molecules, and give some new anticonvulsants by the multiple-target approaches. The results were encouraging, which indicated that the H3R pharmacophore successfully combined to the antiepileptic molecules, maintaining the H3R affinity and anticonvulsant activity, although the anticonvulsant activity decreased compared to the prototypal antiepileptic molecules (Figure 1)29,30.
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.