title: Anticonvulsant effects of isomeric nonimidazole histamine H3receptor 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 H3receptors (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 itsR-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 theS-enantiomer (1), the results show that animals pretreated intraperitoneally (ip) with theR-enantiomer2(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 ligand2was 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 agonistR-(α)-methyl-histamine. Comparisons of the observed antagonistic in vitro affinities among the ligands1-6revealed profound stereoselectivity at human H3Rs with varying preferences for this receptor subtype. Moreover, the in vivo anticonvulsant effects observed in this study for ligands1-6showed stereoselectivity in different convulsion models in male adult rats.
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Bassem
authors.initials: B
authors.lastname: Sadek
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Ali
authors.initials: A
authors.lastname: Saad
authors.affiliation: Biocenter, Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany; Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Johannes Stephan
authors.initials: JS
authors.lastname: Schwed
authors.affiliation: Biocenter, Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany.
authors.forename: Lilia
authors.initials: L
authors.lastname: Weizel
authors.affiliation: Biocenter, Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Walter
authors.affiliation: Biocenter, Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany; Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D001596:Benzylamines / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D054828:Histamine H3 Antagonists / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D010433:Pentylenetetrazole / Q000737:chemistry / Q000494:pharmacology*; D010672:Phenytoin / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018100:Receptors, Histamine H3 / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D014635:Valproic Acid / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000617756:(S)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propaneamide; D000927:Anticonvulsants; D001596:Benzylamines; D054828:Histamine H3 Antagonists; D008024:Ligands; D010880:Piperidines; D018100:Receptors, Histamine H3; D014635:Valproic Acid; D010672:Phenytoin; D010433:Pentylenetetrazole
keywords: H3 receptor; anticonvulsant activity; histamine; isomeric antagonists; stereoselectivity