Anticonvulsant Activity of Enantiomeric N-trans-Cinnamoyl Derivatives of 2-Aminopropan-1-ols and 2-Aminobutan-1-ols.
Epilepsy, one of the most frequent neurological disorders, is still insufficiently treated in about 30% of patients. As a consequence, identification of novel anticonvulsant agents is an important issue in medicinal chemistry. In the present article we report synthesis, physicochemical, and pharmacological evaluation of N-trans-cinnamoyl derivatives of R and S-2-aminopropan-1-ol, as well as R and S-2-aminobutan-1-ol. The structures were confirmed by spectroscopy and for derivatives of 2-aminopropan-1-ols the configuration was evaluated by means of crystallography. The investigated compounds were tested in rodent models of seizures: maximal electroshock (MES) and subcutaneous pentetrazol test (scPTZ), and also in a rodent model of epileptogenesis: pilocarpine-induced status prevention. Additionally, derivatives of 2-aminopropan-1-ols were tested in benzodiazepine-resistant electrographic status epilepticus rat model as well as in vitro for inhibition of isoenzymes of cytochrome P450. All of the tested compounds showed promising anticonvulsant activity in MES. For R(-)-(2E)-N-(1-hydroxypropan-2-yl)-3-phenylprop-2-enamide pharmacological parameters were found as follows: ED50  = 76.7 (68.2-81.3) mg/kg (MES, mice i.p., time = 0.5 h), ED50  = 127.2 (102.1-157.9) mg/kg (scPTZ, mice i.p., time = 0.25 h), TD50  = 208.3 (151.4-230.6) mg/kg (rotarod, mice i.p., time = 0.25 h). Evaluation in pilocarpine status prevention proved that all of the reported compounds reduced spontaneous seizure activity and act as antiepileptogenic agents. Both enantiomers of 2-aminopropan-1-ols did not influence cytochrome P450 isoenzymes activity in vitro and are likely not to interact with CYP substrates in vivo. Chirality 28:482-488, 2016. © 2016 Wiley Periodicals, Inc.
Department of Bioorganic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
Agnieszka
A
Gunia-Krzyżak
Department of Chemistry, Institute of Biology, Pedagogical University, Kraków, Poland.
Ewa
E
Żesławska
Faculty of Chemistry, Jagiellonian University, Kraków, Poland.
Wojciech
W
Nitek
Department of Bioorganic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
Justyna
J
Popiół
Department of Bioorganic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
Henryk
H
Marona
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004597:Electroshock; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010433:Pentylenetetrazole / Q000633:toxicity; D011412:Propanolamines / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology; D013237:Stereoisomerism
D000927:Anticonvulsants; D011412:Propanolamines; C034448:2-aminopropanol; D003577:Cytochrome P-450 Enzyme System; D010433:Pentylenetetrazole
anticonvulsant; cinnamamide; crystal structure; maximal electroshock; pilocarpine status prevention