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Bioorg Med Chem. 2016 Apr 15;24(8):1793-810. doi: 10.1016/j.bmc.2016.03.006. Epub 2016 Mar 3.

Design, physico-chemical properties and biological evaluation of some new N-[(phenoxy)alkyl]- and N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols as anticonvulsant agents.

Author information

1
Department of Bioorganic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland. Electronic address: awaszkie@cm-uj.krakow.pl.
2
Department of Bioorganic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
3
Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
4
Department of Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
5
Laboratory of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
6
Department of Chemistry, Institute of Biology, Pedagogical University, Podchorążych 2, 30-084 Krakow, Poland.
7
Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland.

Abstract

A series of thirty N-(phenoxy)alkyl or N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols has been designed, synthesized and evaluated for anticonvulsant activity in MES, 6Hz test, and pilocarpine-induced status epilepticus. Among the title compounds, the most promising seems R-(-)-2N-{2-[2-(2,6-dimethylphenoxy)ethoxy]ethyl}aminopropan-1-ol hydrochloride (22a) with proved absolute configuration with X-ray analysis and enantiomeric purity. The compound is effective in MES test with ED50=12.92 mg/kg b.w. and its rotarod TD50=33.26 mg/kg b.w. The activity dose is also effective in a neurogenic pain model-the formalin test. Within high throughput profile assay, among eighty one targets, the strongest affinity of the compound is observed towards σ receptors and 5-HT transporter and the compound does not bind to hERG. It also does not exhibit mutagenic properties in the Vibrio harveyi test. Moreover, murine liver microsomal assay and pharmacokinetics profile (mice, iv, p.o., ip) indicate that the liver is the primary site of biotransformation of the compound, suggesting that both 22a and its metabolite(s) are active, compensating probably low bioavailability of the parent molecule.

KEYWORDS:

5-HT; Aminoalkanols; Anticonvulsant activity; MES; Metabolic stability; Mutagenicity; Pharmacokinetics; Seizures; Sigma receptors; Vibrio harveyi

PMID:
26988801
DOI:
10.1016/j.bmc.2016.03.006
[Indexed for MEDLINE]

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