title: Synthesis of New Peptide Derivatives of Galanthamine Designed for Prevention and Treatment of Alzheimer's Disease.
abstract: New derivatives of galanthamine containing peptide fragments with β-secretase inhibitor activity were synthesized. In position 6 of the galanthamine new shortened analogues of β-secretase inhibitor OM 99-2 (Boc-Val-Asn-Leu-Ala-OH and Boc-Val-Asn-Leu-Ala-Val-OH) were included. The new derivatives of the galanthamine in position 11 including Boc and norgalanthamine in P3 or P4 positions, Val in P2' position and benzylamin in P3'-position were also synthesized. All new peptides were investigated on mice for acute toxicity. The test compounds were administered to mice via intraperitoneal (i.p.) route. They have low toxicity (LD50>1000 mg/kg) after i.p. The compound 11-N-demethyl-11-N-N-[Boc-Asp(Asp-Leu-Ala-Val-NH-Bzl)]-Galanthamine was investigated by two way active avoidance method. The compound has good influence on the conditioned reflexes, which improved the processes of learning and memory. Inhibition activity of newly synthesized compounds was monitored against BuChE and IC50 values are determined. All compounds show activity in micromolar concentration. Compounds 5 and 6 have around 10 times higher activity than galanthamine. Compounds 4 and 9 also show good activity. All newly synthesized compounds show low acute toxicity.
authors.affiliation: Department of Organic Chemistry, University of Chemical Technology and Metallurgy, 8 blvd. Kl. Ohridski, Sofia, 1756, Bulgaria. lvezenkov@yahoo.com.
authors.forename: Lyubomir T
authors.initials: LT
authors.lastname: Vezenkov
authors.forename: Lilia
authors.initials: L
authors.lastname: Ilieva
authors.forename: Dancho L
authors.initials: DL
authors.lastname: Danalev
authors.forename: Anastasia
authors.initials: A
authors.lastname: Bakalova
authors.forename: D Nikolay
authors.initials: DN
authors.lastname: Vassilev
authors.forename: Nikolai
authors.initials: N
authors.lastname: Danchev
authors.forename: Irina
authors.initials: I
authors.lastname: Nikolova
mesh_terms: D000544:Alzheimer Disease / Q000517:prevention & control*; D000818:Animals; D005702:Galantamine / Q000138:chemical synthesis* / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D010455:Peptides; D005702:Galantamine