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- Title
Chapter 34: In Vitro and in Vivo Studies on Toxicity and Pharmacological Activity of New L-Valine Peptidomimetics.
- Authors
TANCHEVA, L.; NOVOSELSKI, M.; ENCHEVA, E.; PETKOV, V.; GORNEVA, G.; TSEKOVA, D.; CHEKALAROVA, J.; GURT, I.; KATZ, E.; PAVLOVA, E.
- Abstract
Four newly synthesized peptidomimetics were studied as potential pharmacological agents. The aminoacid L-valine is bound to nicotinic (m-pyridinic) acid - [M] or isonicotinic (p-pyridinic) acid [P] on one side, and to alkyl spacer containing 3 or 6 methylene groups on the other side. Our results show that the compounds are neuropharmacologically active agents (especially 6 - isomers) with low toxicity (in vivo and in vitro) and moderate antiviral activity against Herpes Simplex. The compounds showed a very low toxicity in vivo (in Albino mice) (intraperitoneal and oral- over 2 000 mg/kg, and cytotoxicity lower than this of vitamin C) and also in vitro (in cell culture); as well as a good therapeutic index (over 8). Established antiviral activity against herpes simplex was moderate and is probably related to their chelating activity. Two of compounds (M6 and P6) increased processes of learning and memory in mice and had significant analgesic effect. Their high lipid solubility is probably responsible for their CNS-affinity. M6 and P6 had a higher log P than M3 and P3 (in system octanol/water) and they had better analgesic and anticonvulsant activity in vivo than compounds with 3 spacers. The compounds had the ability to modify the effects of some CNSdrugs. In acute treatment hexobarbital narcosis was prolonged by P6 and M6, but after 5 days of treatment they shortened it significantly. The mechanism of interaction is probably not only on the CNS level, but on the metabolic level too (affecting hepatic P-450- monooxygenases). The differences and varieties in their effects obviously are due to their positional and structure isomery.
- Subjects
VALINE; BRANCHED chain amino acids; PHARMACOLOGY; NIACIN; NOOTROPIC agents; DRUG development; HERPES simplex prevention; ANALGESICS; ANTICONVULSANTS
- Publication
Journal of Medical Chemical, Biological & Radiological Defense, 2010, Vol 8, p266
- ISSN
1540-6709
- Publication type
Article