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Novel naphthyloxy derivatives - Potent histamine H 3 receptor ligands. Synthesis and pharmacological evaluation.
- 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.)
- Subjects :
- Analgesics administration & dosage
Analgesics chemical synthesis
Analgesics pharmacology
Analgesics toxicity
Animals
Antazoline pharmacology
Anticonvulsants administration & dosage
Anticonvulsants chemical synthesis
Anticonvulsants toxicity
Atropine pharmacology
Azepines administration & dosage
Azepines chemical synthesis
Azepines toxicity
Dose-Response Relationship, Drug
Guinea Pigs
HEK293 Cells
Histamine H3 Antagonists administration & dosage
Histamine H3 Antagonists chemical synthesis
Histamine H3 Antagonists toxicity
Humans
Ligands
Male
Mice
Naphthalenes administration & dosage
Naphthalenes chemical synthesis
Naphthalenes toxicity
Piperidines administration & dosage
Piperidines chemical synthesis
Piperidines toxicity
Rats, Wistar
Receptor, Muscarinic M3 metabolism
Receptors, Histamine H1 metabolism
Receptors, Histamine H3 metabolism
Anticonvulsants pharmacology
Azepines pharmacology
Histamine H3 Antagonists pharmacology
Naphthalenes pharmacology
Piperidines pharmacology
Subjects
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