Synthesis and antiseizure effect evaluation of nonimidazole histamine H3 receptor antagonists containing the oxazole moiety

• Published in: Archiv der Pharmazie (Weinheim) 2021-04, Vol.354 (4), p.e2000298-n/a
• Main Authors: Xiao, Feng, Yan, Rui, Zhang, Yanhui, Wang, Shiben, Chen, Shilong, Zhou, Naiming, Deng, Xianqing
• Format: Article
• Language: English
• Subjects: antiseizure; epilepsy; H3 receptor antagonists; Histamine; oxazole derivatives
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202000298

The use of histamine H3 receptor (H3R) antagonists is becoming a promising therapeutic approach for epilepsy. In this paper, a series of novel nonimidazole H3R antagonists was synthesized and screened as antiepileptic drugs. All of these prepared antagonists displayed micromolar or submicromolar H3R antagonistic activities in the cAMP response element luciferase screening assay. Compounds 5a (IC50 = 0.11 μM), 5b (IC50 = 0.56 μM), and 5f (IC50 = 0.78 μM) displayed the most potent H3R antagonistic activities, with considerable potency when compared with pitolisant (IC50 = 0.51 μM). In the maximal electroshock (MES)‐induced seizure model, compounds 5c, 5e, and 5g showed obvious protection for the electrostimulated mice, and the protection of 5g against the MES‐induced seizures was fully abrogated when mice were cotreated with R‐(α)‐methyl‐histamine, a central nervous system‐penetrant H3R agonist, suggesting that the potential therapeutic effect of 5g was observed to work through H3R. These results indicate that the attempt to find a new antiepileptic drug among H3R antagonists is practicable, but it is necessary to consider the log P of the molecules to ensure penetration of the blood–brain barrier. A series of novel nonimidazole histamine H3 receptor (H3R) antagonists was synthesized and screened as antiseizure drugs. Some candidates were obtained with micromolar H3R antagonistic activities as compared with pitolisant and potent antiseizure activities in an epileptic animal model (maximal electroshock‐induced seizures). The potential therapeutic effect of 5g is shown to work through H3R.