Synthesis and antiseizure effect evaluation of nonimidazole histamine H₃receptor antagonists containing the oxazole moiety

Abstract

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.

Reproductive and fetal toxicity studies of histamine H3 receptor antagonist DL76 used in mice to prevent maximal electroshock-induced seizure

“…As previously described and with a slight modification in the intensity applied, seizures were elicited in mice with a 50-Hz alternating current of 120 mA intensity ( Kaminski et al, 2015 ; Song et al, 2020 ; Xiao et al, 2021 ; Hua et al, 2023 ). The current was applied through ear electrodes for 0.2 s. Protection against the spread of MES-induced convulsion was defined as the abolition of the tonic hind limb extension (THLE) component of the seizure ( Kaminski et al, 2015 ; Song et al, 2020 ; Xiao et al, 2021 ; Hua et al, 2023 ).…”

“…As previously described and with a slight modification in the intensity applied, seizures were elicited in mice with a 50-Hz alternating current of 120 mA intensity ( Kaminski et al, 2015 ; Song et al, 2020 ; Xiao et al, 2021 ; Hua et al, 2023 ). The current was applied through ear electrodes for 0.2 s. Protection against the spread of MES-induced convulsion was defined as the abolition of the tonic hind limb extension (THLE) component of the seizure ( Kaminski et al, 2015 ; Song et al, 2020 ; Xiao et al, 2021 ; Hua et al, 2023 ). The animals were divided into the following experimental groups, with eight mice in each: the control group injected with saline, the positive control group injected with 300 mg/kg of VPA (the minimal dose of VPA that protected animals against the spread of MES-induced convulsions without mortality in mice) ( Sadek et al, 2015 ; Bastaki et al, 2018 ), and four groups that were administered the test compound DL76 at doses of 7.5 mg/kg, 15 mg/kg, 30 mg/kg, or 60 mg/kg.…”

Antiseizure Properties of Histamine H3 Receptor Antagonists Belonging 3,4-Dihydroquinolin-2(1H)-Ones

“…One of the two test models is the MES seizure model, another is the PTZ-induced seizure model. In our previous work, we found that the synthetic H3R antagonists and PIT showed an antiseizure activity at 10 mg/kg [22]. In addition, the administration of this dosage can minimize the impact of other possible side effects such as central inhibition and cardiac toxicity.…”

“…In our previous work, dozens of 2-methyl-4-phenyloxazoles were designed and synthesized as new H 3 R antagonists [22]. All these compounds showed micromolar to submicromolar H 3 R antagonistic activities.…”

Ultrasonic-induced synthesis of novel diverse arylidenes via Knoevenagel condensation reaction. Antitumor, QSAR, docking and DFT assessment

“…In the field of heterocyclic compounds designation, there has been a markedly increased interest in the invention of new heterocyclic compounds, especially nitrogen-bearing ones, because of their prevalence in nature and also in pharmacology. Piperidine moiety is a generative basis of numerous therapeutically important compounds due to its numerous biological and pharmacological activities 1,2 including anticancer 3–5 anti-proliferative compounds against MCF-7 breast cancer and PC-3 prostate, HepG2 cancer cells, 6 antidiabetic, 7 antidepressant, 8 H 3 R antagonistic, 9 antibacterial, 10 antifungal, 11,12 antiviral, anti-HIV, antineoplastic, 7 α 2 c antagonists, 13 anesthetics, 14 anti-inflammatory, 15,16 hypotensive, 17 antituberculosis 18 and analgesic agent. 19 Moreover, piperidine complexes represent one of the most ubiquitous heterocyclic moieties existing in food and drug administration (FDA-approved drugs) (Fig.…”