title: Non-imidazole histamine H3 receptor ligands incorporating antiepileptic moieties.
abstract: A small series of histamine H3 receptor (H3R) ligands (1-5) incorporating different antiepileptic structural motifs has been newly synthesized. All compounds exhibited moderate to high in vitro hH3R affinities up to a sub-nanomolar concentration range with pKi values in the range of 6.25-9.62 with varying preferences for this receptor subtype. The compounds (1-5) were further investigated in vivo on anticonvulsant effects against maximum electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled convulsions in rats having phenytoin (PHT) as the reference antiepileptic drug (AED). Surprisingly, animals pretreated with 1 mg/kg, i.p. of 5,5-diphenyl-3-(3-(piperidin-1-yl)propyl)imidazolidine-2,4-dione (4) were only moderately protected and no protection was observed for compounds 1-3 and 5 in three different doses (1 mg, 5 mg, and 10 mg/kg i.p.). Compound 4 (1 mg/kg, i.p.) failed to modify PTZ-kindled convulsion. However, a dose of 10 mg/kg significantly reduced convulsions in both models. In contrast, 5,5-diphenyl-3-(4-(3-(piperidin-1-yl)propoxy)benzyl)imidazolidine-2,4-dione (5) (1, 5, and 10 mg/kg, i.p.) showed proconvulsant effects in the MES model with further confirmation of these results in the PTZ model as no protection was observed against convulsion in the doses tested (1 and 10 mg/kg). In addition, compound 4 (10 mg/kg, i.p.) significantly prolonged myoclonic latency time and shortened total convulsion duration when compared to control, PHT or standard H3R inverse agonist/antagonist pitolisant (PIT). Our results showed that H3R pharmacophores could successfully be structurally combined to antiepileptic moieties, especially phenytoin partial structures, maintaining the H3R affinity. However, the new derivatives for multiple-target approaches in epilepsy models are complex and show that pharmacophore elements are not easily pharmacologically combinable.
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine & Health Sciences, P.O. Box 17666, Al Ain 0097, United Arab Emirates University, United Arab Emirates. Electronic address: bassem.sadek@uaeu.ac.ae.
authors.forename: Bassem
authors.initials: B
authors.lastname: Sadek
authors.affiliation: Biocenter, Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Universitaetsstr. 1, 40225 Duesseldorf, Germany.
authors.forename: Johannes Stephan
authors.initials: JS
authors.lastname: Schwed
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine & Health Sciences, P.O. Box 17666, Al Ain 0097, United Arab Emirates University, United Arab Emirates.
authors.forename: Dhanasekaran
authors.initials: D
authors.lastname: Subramanian
authors.affiliation: Biocenter, Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
authors.forename: Lilia
authors.initials: L
authors.lastname: Weizel
authors.affiliation: Biocenter, Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Walter
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine & Health Sciences, P.O. Box 17666, Al Ain 0097, United Arab Emirates University, United Arab Emirates.
authors.forename: Abdu
authors.initials: A
authors.lastname: Adem
authors.affiliation: Biocenter, Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Universitaetsstr. 1, 40225 Duesseldorf, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D054828:Histamine H3 Antagonists; D008024:Ligands; D018100:Receptors, Histamine H3
keywords: Anticonvulsant activity; Convulsion; Epilepsy; GPCR; H(3) receptor; Histamine; Pharmacophore elements; Phenytoin