Anticonvulsant and procognitive properties of the non-imidazole histamine H3 receptor antagonist DL77 in male adult rats

Sadek, Bassem; Saad, Ali; Dhanasekaran, Subramanian; Shafiullah, Mohamed; Łażewska, Dorota; Kieć-Kononowiczc, Katarzyna

doi:10.1016/j.neuropharm.2015.10.023

Cited by 62 publications

(101 citation statements)

References 67 publications

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“…The MES test is linked with the electrical induction of the convulsion, whereas the PTZ and STR tests involve chemical induction to generate the convulsion 39,51. The H 3 R ligands ( 1 – 6 ) were administered IP to the rats at doses of 10 mg/kg in the MES, PTZ, and STR screens.…”

Section: Discussionmentioning

confidence: 99%

“…To explore the mechanism of how most promising compounds influences MES-induced convulsions, we have selected the most effective dose of 3 for further analysis. In one group of animals of eight rats, the selected dose of 3 coinjected together with RAMH 10 mg/kg 5 minutes apart and as described previously 31,38,39,41,48–50. All doses were selected according to previously described methods 31,38,41,47.…”

Section: Methodsmentioning

confidence: 99%

“…PTZ 60 mg/kg or STR 3.5 mg/kg was administered IP to all groups (six to eight rats per group), ie, saline and treated rats. Vehicle or tested compounds (VPA 100 or 300 mg/kg in PTZ and STR, respectively,39 PIT 10 mg/kg, or test compounds 1 – 6 at 10 mg/kg, all IP) were administered 30 minutes before PTZ or STR injection. All doses of test compounds were selected according to previously described methods 51–55.…”

Section: Methodsmentioning

confidence: 99%

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Anticonvulsant effects of isomeric nonimidazole histamine H<sub>3</sub> receptor antagonists

Sadek

Saad

Schwed

et al. 2016

DDDT

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Anticonvulsant effects of isomeric nonimidazole histamine H<sub>3</sub> receptor antagonists

Sadek

Saad

Schwed

et al. 2016

DDDT

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“…Furthermore, a marketed application (WakixR) for pitolisant was approved in November 2015 by the European Medical Agency as orphan drug for narcolepsy. Interestingly, results observed in preclinical experiments showed that the H3R antagonist DL-77, a compound structurally strongly related to pitolisant, improves cognitive performance through actions on different memory stages, demonstrating the possible implication of H3Rs for the treatment of neuropsychiatric disorders associated with cognitive symptoms emerging with the chronic use of antiepileptic drugs [109]. PF-03654746 is a potent H3R antagonist and was found to be effective in several experimental object recognition models ( Figure 10, Table 1) [52,106,107].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

“…Furthermore, the development of DL-77, a potent non-imidazole histamine H3R antagonist, has recently succeeded (Figure 10, Table 3) [156] with high antagonist affinities for human histamine H3Rs [156,162], and the results revealed its promising anticonvulsant activity in a maximal electroshock-induced seizure model with a protective action comparable to that of the reference AED phenytoin [24,109]. H3R antagonists are progressing well in clinical trials in the field of epilepsy.…”

Section: Epilepsymentioning

confidence: 99%

Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases

Sadek

Saad

Sadeq

et al. 2016

Behavioural Brain Research

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Design, Synthesis, and Docking Study of Pyrimidine–Triazine Hybrids for GABA Estimation in Animal Epilepsy Models

Sahu

Siddiqui

Naim

et al. 2017

Archiv der Pharmazie

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A series of new pyrimidine-triazine hybrids (4a-t) was designed and synthesized, from which potent anticonvulsant agents were identified. Most of the compounds exhibited promising anticonvulsant activity against the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests, along with minimal motor impairment with higher safety compared to the standard drugs, phenytoin and carbamazepine. In the series, 5-(4-(4-fluorophenyl)-6-(4-hydroxyphenyl)-2-thioxo-5,6-dihydropyrimidin-1(2H)-yl)-1,2-dihydro-1,2,4-triazin-3(6H)-one (4o) and 5-(6-(4-hydroxy-3-methoxyphenyl)-4-(4-hydroxyphenyl)-2-thioxo-5,6-dihydropyrimidin-1(2H)-yl)-1,2-dihydro-1,2,4-triazin-3(6H)-one (4s) emerged as most potent anticonvulsant agents with median doses of 22.54 and 29.40 mg/kg (MES ED ), 285.02 and 293.42 mg/kg (scPTZ ED ), and 389.11 and 412.16 mg/kg (TD ), respectively. Docking studies were also performed for all synthesized compounds to get insight into the binding pattern toward the GABA receptor as a possible mechanism of their anticonvulsant action, and in silico ADME studies were carried out to predict the safety and stability of the molecules. The increased GABA level in the experimental animals in the neurochemical estimation assay confirmed their GABAergic modulating activity. The most potent compounds were also evaluated for their neurotoxic and hepatotoxic effects. Fortunately, they did not show any sign of neurotoxicity or hepatotoxicity, suggesting that they have a broad spectrum of anticonvulsant activity with a large safety margin. Together, this research suggested that 4o and 4s may serve as leads in the discovery and development of new anticonvulsant drugs.

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Anticonvulsant and procognitive properties of the non-imidazole histamine H3 receptor antagonist DL77 in male adult rats

Cited by 62 publications

References 67 publications

Anticonvulsant effects of isomeric nonimidazole histamine H<sub>3</sub> receptor antagonists

Anticonvulsant effects of isomeric nonimidazole histamine H<sub>3</sub> receptor antagonists

Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases

Design, Synthesis, and Docking Study of Pyrimidine–Triazine Hybrids for GABA Estimation in Animal Epilepsy Models

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