Back to Search Start Over

Novel naphthyloxy derivatives - Potent histamine H 3 receptor ligands. Synthesis and pharmacological evaluation.

Authors :
Łażewska D
Kaleta M
Hagenow S
Mogilski S
Latacz G
Karcz T
Lubelska A
Honkisz E
Handzlik J
Reiner D
Satała G
Filipek B
Stark H
Kieć-Kononowicz K
Source :
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2018 May 15; Vol. 26 (9), pp. 2573-2585. Date of Electronic Publication: 2018 Apr 11.
Publication Year :
2018

Abstract

A series of 1- and 2-naphthyloxy derivatives were synthesized and evaluated for histamine H <subscript>3</subscript> receptor affinity. Most compounds showed high affinities with K <subscript>i</subscript> values below 100 nM. The most potent ligand, 1-(5-(naphthalen-1-yloxy)pentyl)azepane (11) displayed high affinity for the histamine H <subscript>3</subscript> receptor with a K <subscript>i</subscript> value of 21.9 nM. The antagonist behaviour of 11 was confirmed both in vitro in the cAMP assay (IC <subscript>50</subscript>  = 312 nM) and in vivo in the rat dipsogenia model (ED <subscript>50</subscript>  = 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 ED <subscript>50</subscript>  = 30.6 mg/kg (early phase) and ED <subscript>50</subscript>  = 20.8 mg/kg (late phase). Another interesting compound, 1-(5-(Naphthalen-1-yloxy)pentyl)piperidine (13; H <subscript>3</subscript> R K <subscript>i</subscript>  = 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 ED <subscript>50</subscript> 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 ED <subscript>50</subscript> of 33.1 mg/kg and (44 mA) ED <subscript>50</subscript> 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 H <subscript>3</subscript> receptor ligands with promising in vitro and in vivo activity.<br /> (Copyright © 2018. Published by Elsevier Ltd.)

Details

Language :
English
ISSN :
1464-3391
Volume :
26
Issue :
9
Database :
MEDLINE
Journal :
Bioorganic & medicinal chemistry
Publication Type :
Academic Journal
Accession number :
29681486
Full Text :
https://doi.org/10.1016/j.bmc.2018.04.023