title: Synthesis and biological activity of novel tert-amylphenoxyalkyl (homo)piperidine derivatives as histamine H3R ligands.
abstract: As a continuation of our search for novel histamine H3receptor ligands a series of twenty new tert-amyl phenoxyalkylamine derivatives (2-21) was synthesized. Compounds of four to eight carbon atoms spacer alkyl chain were evaluated on their binding properties at human histamine H3receptor (hH3R). The highest affinities were observed for pentyl derivatives 6-8 (Ki=8.8-23.4nM range) and among them piperidine derivative 6 with Ki=8.8nM. Structures 6, 7 were also classified as antagonists in cAMP accumulation assay (with EC50=157 and 164nM, respectively). Moreover, new compounds were also evaluated for anticonvulsant activity in Antiepileptic Screening Program (ASP) at National Institute of Neurological Disorders and Stroke (USA). Seven compounds (2-4, 9, 11, 12 and 20) showed anticonvulsant activity at maximal electroshock (MES) test in the dose of 30mg/kg at 0.5h. In the subcutaneous pentetrazole (scMET) test compound 4 showed protection at 100 and 300mg/kg dose at mice, however compounds showed high neurotoxicity in rotarod test at used doses. Also, molecular modeling studies were undertaken, to explain affinity of compounds at hH3R (taking into the consideration X-ray analysis of compound 18). In order to estimate "drug-likeness" of selected compounds in silico and experimental evaluation of lipophilicity, metabolic stability and cytotoxicity was performed.
authors.affiliation: Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
authors.forename: Kamil J
authors.initials: KJ
authors.lastname: Kuder
authors.affiliation: Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Łażewska
authors.affiliation: Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Kaleta
authors.affiliation: Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
authors.forename: Gniewomir
authors.initials: G
authors.lastname: Latacz
authors.affiliation: Institute of Pharmaceutical Chemistry, Biozentrun, ZAFES, Frankfurt/Main 60438, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Kottke
authors.affiliation: Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Olejarz
authors.affiliation: Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Karcz
authors.affiliation: Institute of General and Ecological Chemistry, Technical University of Łódź, Żeromskiego 116 str., Łódź 90-924, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Fruziński
authors.affiliation: Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Szczepańska
authors.affiliation: Institute of General and Ecological Chemistry, Technical University of Łódź, Żeromskiego 116 str., Łódź 90-924, Poland.
authors.forename: Janina
authors.initials: J
authors.lastname: Karolak-Wojciechowska
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University, Universitaetsstr. 1, Düsseldorf 40225, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.affiliation: Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland. Electronic address: mfkonono@cyf-kr.edu.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004597:Electroshock; D057809:HEK293 Cells; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D009474:Neurons / Q000187:drug effects; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility
chemical_list: D000927:Anticonvulsants; D054828:Histamine H3 Antagonists; D010880:Piperidines; D018100:Receptors, Histamine H3
keywords: Anticonvulsants; Drug-like properties; Histamine H(3) receptor; Histamine H(3) receptor ligands; Molecular docking; Non-imidazole histamine H(3)R ligands; Piperidine derivatives