title: Design, physico-chemical properties and biological evaluation of some new N-[(phenoxy)alkyl]- and N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols as anticonvulsant agents.
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.
authors.affiliation: Department of Bioorganic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland. Electronic address: awaszkie@cm-uj.krakow.pl.
authors.forename: A M
authors.initials: AM
authors.lastname: Waszkielewicz
authors.affiliation: Department of Bioorganic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Gunia-Krzyżak
authors.affiliation: Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
authors.forename: B
authors.initials: B
authors.lastname: Powroźnik
authors.affiliation: Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Słoczyńska
authors.affiliation: Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
authors.forename: E
authors.initials: E
authors.lastname: Pękala
authors.affiliation: Department of Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Walczak
authors.affiliation: Laboratory of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Bednarski
authors.affiliation: Department of Chemistry, Institute of Biology, Pedagogical University, Podchorążych 2, 30-084 Krakow, Poland.
authors.forename: E
authors.initials: E
authors.lastname: Żesławska
authors.affiliation: Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland.
authors.forename: W
authors.initials: W
authors.lastname: Nitek
authors.affiliation: Department of Bioorganic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
authors.forename: H
authors.initials: H
authors.lastname: Marona
mesh_terms: D000605:Amino Alcohols / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002627:Chemistry, Physical; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D010862:Pilocarpine
chemical_list: D000605:Amino Alcohols; D000927:Anticonvulsants; D010862:Pilocarpine
keywords: 5-HT; Aminoalkanols; Anticonvulsant activity; MES; Metabolic stability; Mutagenicity; Pharmacokinetics; Seizures; Sigma receptors; Vibrio harveyi