Anticonvulsant effects of isomeric nonimidazole histamine H₃ receptor antagonists

Abstract

Phenytoin (PHT), valproic acid, and modern antiepileptic drugs (AEDs), eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%–80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H3 receptors (H3Rs) for epilepsy might be a promising therapeutic approach. To determine the potential of H3Rs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the (S)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propanamide (1). In continuation of our research, we asked whether anticonvulsant differences in activities will be observed for its R-enantiomer, namely, (R)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propaneamide (2) and analogs thereof, in maximum electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced convulsion models in rats having PHT and valproic acid (VPA) as reference AEDs. Unlike the S-enantiomer (1), the results show that animals pretreated intraperitoneally (ip) with the R-enantiomer 2 (10 mg/kg) were moderately protected in MES and STR induced models, whereas proconvulsant effect was observed for the same ligand in PTZ-induced convulsion models. However, animals pretreated with intraperitoneal doses of 5, 10, or 15 mg/kg of structurally bulkier (R)-enantiomer (3), in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-yl)propoxy)phenyl)methanol, and its (S)-enantiomer (4) significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the (R)-enantiomer (3) in MES model were significantly greater than those of the standard H3R inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and reversed when rats were pretreated with the selective H3R agonist R-(α)-methyl-histamine. Comparisons of the observed antagonistic in vitro affinities among the ligands 1–6 revealed profound stereoselectivity at human H3Rs with varying preferences for this receptor subtype. Moreover, the in vivo anticonvulsant effects observed in this study for ligands 1–6 showed stereoselectivity in different convulsion models in male adult rats.

Anticonvulsant and reproductive toxicological studies of the imidazole-based histamine H3R antagonist <strong>2-18</strong> in mice

“… 10 , 11 , 13 – 16 , 30 , 31 The current was applied through ear electrodes for 1 s. Protection against the spread of MES-induced convulsion was defined as the abolition of the tonic hind limb extension (THLE) component of the convulsion. 10 , 11 , 13 , 15 , 32 , 33 The animals were divided into groups of eight mice. In the positive control group, mice were injected with VPA at a previously described dose of 300 mg/kg, this being the minimal dose of VPA that protected animals against the spread of MES-induced convulsions without mortality in mice.…”

“… 10 – 12 Both major and minor malformations have been attributed to antiepileptic drugs (AEDs). 10 , 13 In addition, many epilepsy patients may also have cognitive problems in addition to suffering from seizures, 14 – 16 with the most common cognitive problem being memory deficit. 2 , 17 While the causes of reduced memory functions in patients with epilepsy have not yet been completely elucidated, the forms and frequencies of seizures and the side effects of AEDs at therapeutic doses have been described.…”

The Histamine H3 Receptor Antagonist E159 Reverses Memory Deficits Induced by Dizocilpine in Passive Avoidance and Novel Object Recognition Paradigm in Rats

“…The E159-provided procognitive effect was confirmed by conducting additional experiments in which the respective promising dose of E159 (2.5 mg/kg) and PYR (10 mg/kg), ZOL (10 mg/kg), SCO (1 mg/kg), or a combination of SCO and ZOL were co-injected. The doses of SCO, PYR, and ZOL were selected according to previous studies ( Orsetti et al, 2001 , 2002 ; Khan et al, 2015 ; Sadek et al, 2015 , 2016a , b , d ) ( Figures 2 – 4 ).…”

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

“…Therefore, evaluating numerous oxidative stress markers (e.g., malondialdehyde (MDA), glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD)) of PTZ-kindled animals were carried out to assess the effects of the novel H3R antagonist E177. Furthermore, and amongst all the brain regions, the hippocampus has gained attention in the PTZ model as it contains several distinct neuronal circuits related to seizure genesis [54][55][56][57][58][59]. In the present study, the capability of H3R antagonist E177 to attenuate oxidative stress markers was evaluated in hippocampus tissues of PTZ-kindled rats ( Figure 4A P < 0.05], respectively, and increased GSH levels, with [F (1,10) = 96.74; P < 0.001] and [F (1,10) = 356.1; P < 0.001], respectively, and as compared with PTZ-kindled rats.…”

“…Moreover, chronic pretreatment of RAM to control rats also did not significantly alter oxidative stress statues, with [F ( Several preclinical studies revealed the potential memory-enhancing effect of numerous H3R antagonists [16,18,21,26,[55][56][57][58][59] capable of modulating the release of brain histamine (HA) by antagonizing H3 auto-receptors, and numerous other brain neurotransmitters, e.g., acetylcholine (ACh), γ-aminobutyric acid (GABA), and glutamate (GLU) by antagonizing H3 hetero-receptors in different brain regions [60][61][62].…”