Non-imidazole-based histamine H3 receptor antagonists with anticonvulsant activity in different seizure models in male adult rats

Abstract

A series of twelve novel non-imidazole-based ligands (3–14) was developed and evaluated for its in vitro binding properties at the human histamine H3 receptor (hH3R). The novel ligands were investigated for their in vivo protective effects in different seizure models in male adult rats. Among the H3R ligands (3–14) tested, ligand 14 showed significant and dose-dependent reduction in the duration of tonic hind limb extension in maximal electroshock (MES)-induced seizure model subsequent to acute systemic administration (5, 10, and 20 mg/kg, intraperitoneally), whereas ligands 4, 6, and 7 without appreciable protection in MES model were most promising in pentylenetetrazole (PTZ) model. Moreover, the protective effect observed for ligand 14 in MES model was lower than that observed for the reference drug phenytoin and was entirely abrogated when rats were co-administered with the brain-penetrant H1R antagonist pyrilamine (PYR) but not the brain-penetrant H2R antagonist zolantidine (ZOL), demonstrating that histaminergic neurotransmission by activation of postsynaptically located H1Rs seems to be involved in the protective action. On the contrary, PYR and ZOL failed to abrogate the full protection provided by 4 in PTZ model and the moderate protective effect by 14 in strychnine (STR) model. Moreover, the experimental and in silico estimation of properties such as metabolism was performed for five selected test compounds. Also, lipophilicity using planar reversed-phase thin-layer chromatography method was included for better understanding of the molecular properties of the tested compounds. Additionally, the absorption, distribution, metabolism, and elimination and toxicity parameters were evaluated for the most promising compounds 2, 4, 6, 7, and 14 utilizing in vitro methods. These interesting results highlight the potential of H3R ligands as new antiepileptic drugs or as adjuvants to available epilepsy medications.

Enigmatic Histamine Receptor H4 for Potential Treatment of Multiple Inflammatory, Autoimmune, and Related Diseases

“…A plethora of studies have related the heterogenic and complex pharmacology of histamine receptors to various diseases: H 1 R to the allergic inflammation, anaphylaxis, and motion sickness [28,29], H 2 R to the stimulation of gastric acid secretion leading to peptic ulcer, GERD and aspiration pneumonitis [30,31], H 3 R to the neurotransmission controlling sleep, cognitive processes, schizophrenia, epilepsy, and pain [32][33][34][35][36][37], and H 4 R to the immune responses (cancers, myocarditis) and inflammation [38][39][40][41][42] (Figure 2). The H 3 and H 4 receptors have relatively high affinity for histamine (5-10 nM) compared to the low affinity of H 1 R and H 2 R which is in the µM range [6,43].…”

Antagonism of Histamine H3 receptors Alleviates Pentylenetetrazole-Induced Kindling and Associated Memory Deficits by Mitigating Oxidative Stress, Central Neurotransmitters, and c-Fos Protein Expression in Rats

“…Interestingly, in the past decades histamine H3 receptor (H3R) antagonists/ inverse agonists obtained an enormous attention regarding their possible diverse applications in the treatment of different neuropsychiatric diseases including epilepsy, dementia, Alzheimer's disease, autism spectrum disorder and cognitive impairment [16][17][18][19][20][21][22][23]. This owing to H3Rs unique feature by acting as autoreceptors through regulating the synthesis and release of histamine [24], in addition to acting as heteroreceptors by regulating the release of other neurotransmitters (e.g., acetylcholine, serotonin, noradrenalin and others) [23].…”

“…This owing to H3Rs unique feature by acting as autoreceptors through regulating the synthesis and release of histamine [24], in addition to acting as heteroreceptors by regulating the release of other neurotransmitters (e.g., acetylcholine, serotonin, noradrenalin and others) [23]. Moreover, other studies have indicated the protective effect of H3R antagonists/ inverse agonists in different acute seizures models including maximal electroshock (MES) and PTZ-induced seizure models [19,[25][26][27]. Furthermore, the procognitive effect of H3R antagonists/ inverse agonists was confirmed lately by applying different behavioral tests including inhibitory avoidance paradigm (IAP), novel object recognition test (NOR) and Morris water maze test (MWM) [20,26,[28][29][30].…”

Selenazolinium Salts as “Small Molecule Catalysts” with High Potency against ESKAPE Bacterial Pathogens

“…In order to assess some central drug-safety properties for the selenium agents ( 1 – 8 and ebselen), and bearing in mind that certain inorganic-selenium compounds such as selenite (SeO 3 2− ) interact unfavourably with DNA, all relevant compounds were investigated for their possible mutagenic properties in vitro employing the microtiter Ames test [ 25 , 26 , 27 , 28 , 29 ].…”