title: The anticonvulsant, local anesthetic and hemodynamic properties of some chiral aminobutanol derivatives of xanthone.
abstract: In the present study, several pharmacological tests in animals were carried out to assess potential anticonvulsant, local anesthetic and hemodynamic activity of novel 2- and 4-substituted aminobutanol chiral derivatives of xanthone (hydrochlorides of: (R,S)-2-[(7-chloro)-2-xanthonemethyl)]-N-methylaminobutan-1-ol (MH-2(R,S)), (R,S)-2-(4-xanthonemethyl)-aminobutan-1-ol (MH-20(R,S)) and (R,S)-2-[(6-methoxy)-2-xanthonemethyl]-aminobutan-1-ol (MH-26(R,S)) and their pure enantiomers R and S). The obtained results provided evidence that the most interesting anticonvulsant (in maximal electroshock-test) activity was shown by compound MH-2(R), which in dose 100 mg/kg p.o., protected the mice against tonic cramp of extensors similarly as phenytoin. Moreover, this compound, in concentrations from 0.25 to 1%, also possessed high local anesthetic activity (in infiltration anesthesia), comparable to the reference compound, mepivacaine. All examined compounds suppressed the spontaneous locomotor activity in mice, especially compound MH-2(R,S) and MH-20(R,S), and their enantiomers. The impairment of motor coordination (in chimney test) for applied doses was not observed. Furthermore, compound MH-20(S) at dose corresponding to 1/10 LD50 displayed an interesting hemodynamic activity and significantly decreased systolic and diastolic blood pressure in rats. All examined compounds showed chronotropic negative effect in anesthetized rats ECG record. The most reducing heart frequency was observed for enantiomers S of aminobutanol derivatives of xanthone, especially MH-2(S). The LD50 values of the investigated compounds were comparable with LD50 value of the reference compound in local anesthesia tests--mepivacaine. These studies demonstrated different strength of enantiomers and racemic mixture in carried out tests, where the R enantiomers presented rather central and local anesthetic properties, whereas S enatiomers influenced the hemodynamic activity.
authors.affiliation: Department of Pharmacodynamics, Collegium Medicum, Jagiellonian University, 9 Medyczna Str., 30-688 Kraków, Poland. mfwiesek@cyf-kr.edu.pl
authors.forename: Magdalena
authors.initials: M
authors.lastname: Jastrzebska-Wiesek
authors.forename: Ryszard
authors.initials: R
authors.lastname: Czarnecki
authors.forename: Henryk
authors.initials: H
authors.lastname: Marona
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D000440:Butanols / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects*; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D044004:Xanthones / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000779:Anesthetics, Local; D000927:Anticonvulsants; D000440:Butanols; D044004:Xanthones