Novel compounds designed as antistress agents.
Agents against biologic stress were designed, containing GABA esterified with lorazepam and amidated with (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (5) or 3,5-di-tert-butyl-4-hydroxybenzoic acid (6). Compounds 5 and 6 inhibited lipid peroxidation, IC(50) 1.1 and 24 microM. Oxidative damage accompanied stress, 5 and 6 reduced radical attack, uropepsinogen, and morphological changes. Stress increased drug metabolism. Treatment with 5 reduced cytochrome P450 and N-demethylation of erythromycin, 35 and 40%. Compounds 5 and 6 decreased lipidemic indices of hyperlipidemic rats 40-63%.
Tsiakitzis
Karyophyllis C
KC
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, 54124 Thessaloniki, Greece.
Rekka
Eleni A
EA
Kourounakis
Angeliki P
AP
Kourounakis
Panos N
PN
D000577:Amides / Q000737:chemistry; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001565:Benzoates / Q000737:chemistry; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002264:Carboxylic Acids / Q000737:chemistry; D002839:Chromans / Q000737:chemistry; D015195:Drug Design; D050171:Dyslipidemias / Q000188:drug therapy / Q000378:metabolism; D004951:Esterification; D015227:Lipid Peroxidation / Q000187:drug effects; D008140:Lorazepam / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D013312:Stress, Physiological / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000577:Amides; D014151:Anti-Anxiety Agents; D000975:Antioxidants; D001565:Benzoates; D002264:Carboxylic Acids; D002839:Chromans; D005680:gamma-Aminobutyric Acid; D008140:Lorazepam; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid