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Bioorg Med Chem. 2018 May 15;26(9):2573-2585. doi: 10.1016/j.bmc.2018.04.023. Epub 2018 Apr 11.

Novel naphthyloxy derivatives - Potent histamine H3 receptor ligands. Synthesis and pharmacological evaluation.

Author information

1
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address: dlazewska@cm-uj.krakow.pl.
2
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
3
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
4
Department of Pharmacodynamic, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
5
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
6
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address: mfkonono@cyf-kr.edu.pl.

Abstract

A series of 1- and 2-naphthyloxy derivatives were synthesized and evaluated for histamine H3 receptor affinity. Most compounds showed high affinities with Ki values below 100 nM. The most potent ligand, 1-(5-(naphthalen-1-yloxy)pentyl)azepane (11) displayed high affinity for the histamine H3 receptor with a Ki value of 21.9 nM. The antagonist behaviour of 11 was confirmed both in vitro in the cAMP assay (IC50 = 312 nM) and in vivo in the rat dipsogenia model (ED50 = 3.68 nM). Moreover, compound 11 showed positive effects on scopolamine induced-memory deficits in mice (at doses of 10 and 15 mg/kg) and an analgesic effect in the formalin test in mice with ED50 = 30.6 mg/kg (early phase) and ED50 = 20.8 mg/kg (late phase). Another interesting compound, 1-(5-(Naphthalen-1-yloxy)pentyl)piperidine (13; H3R Ki = 53.9 nM), was accepted for Anticonvulsant Screening Program at the National Institute of Neurological Disorders and Stroke/National Institute of Health (Rockville, USA). The screening was performed in the maximal electroshock seizure (MES), the subcutaneous pentylenetetrazole (scPTZ) and the 6-Hz psychomotor animal models of epilepsy. Neurologic deficit was evaluated by the rotarod test. Compound 13 inhibited convulsions induced by the MES with ED50 of 19.2 mg/kg (mice, i.p.), 17.8 (rats, i.p.), and 78.1 (rats, p.o.). Moreover, 13 displayed protection against the 6-Hz psychomotor seizures (32 mA) in mice (i.p.) with ED50 of 33.1 mg/kg and (44 mA) ED50 of 57.2 mg/kg. Furthermore, compounds 11 and 13 showed in vitro weak influence on viability of tested cell lines (normal HEK293, neuroblastoma IMR-32, hepatoma HEPG2), weak inhibition of CYP3A4 activity, and no mutagenicity. Thus, these compounds may be used as leads in a further search for histamine H3 receptor ligands with promising in vitro and in vivo activity.

PMID:
29681486
DOI:
10.1016/j.bmc.2018.04.023
[Indexed for MEDLINE]

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