Novel naphthyloxy derivatives - Potent histamine H3 receptor ligands. Synthesis and pharmacological evaluation.
Bioorg Med Chem
; 26(9): 2573-2585, 2018 05 15.
Article
em En
| MEDLINE
| ID: mdl-29681486
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 100â¯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 21.9â¯nM. The antagonist behaviour of 11 was confirmed both in vitro in the cAMP assay (IC50â¯=â¯312â¯nM) and in vivo in the rat dipsogenia model (ED50â¯=â¯3.68â¯nM). Moreover, compound 11 showed positive effects on scopolamine induced-memory deficits in mice (at doses of 10 and 15â¯mg/kg) and an analgesic effect in the formalin test in mice with ED50â¯=â¯30.6â¯mg/kg (early phase) and ED50â¯=â¯20.8â¯mg/kg (late phase). Another interesting compound, 1-(5-(Naphthalen-1-yloxy)pentyl)piperidine (13; H3R Kiâ¯=â¯53.9â¯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 19.2â¯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 (32â¯mA) in mice (i.p.) with ED50 of 33.1â¯mg/kg and (44â¯mA) ED50 of 57.2â¯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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperidinas
/
Azepinas
/
Antagonistas dos Receptores Histamínicos H3
/
Anticonvulsivantes
/
Naftalenos
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2018
Tipo de documento:
Article