title: Design of new cognition enhancers: from computer prediction to synthesis and biological evaluation.
abstract: To discover new cognition enhancers, a set of virtually designed synthesizable compounds from different chemical series was investigated using two computer-aided approaches. One of the approaches is prediction of biological activity spectra for substances (PASS) and the second is prediction of toxicity, mutagenicity, and carcinogenicity (DEREK). To increase the probability of finding new chemical entities, we investigated a heterogeneous set of highly diverse chemicals including different types of heterocycles: five-membered (thiophenes, thiazoles, imidazoles, oxazoles, pyrroles), six-membered (pyridines, pyrimidines), seven-membered (diazepines, triazepines), fused five+six-membered heterocycles (indoles, benzothiazoles, purines, indolizines, neutral, mesoionic, and cationic azolopyridines). A database including 5494 structures of compounds was created. On the basis of the PASS and DEREK prediction results, eight compounds with the highest probability of cognition-enhancing effect were selected. The cognition-enhancing activity testing showed that all of the selected compounds had a pronounced antiamnesic effect and were found to reduce significantly scopolamine-induced amnesia of passive avoidance reflex (PAR). The action of compounds at doses of 1 and 10 mg/kg caused a statistically significant increase in latent time of reflex and in the number of animals, which did not enter the dark chamber when testing the PAR. Therefore, on the basis of computer prediction, new cognition-enhancing agents were discovered within the chemical series, in which this activity was not known previously.
authors.affiliation: School of Pharmacy, Department of Pharmaceutical Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece. geronik@pharm.auth.gr
authors.forename: Athina A
authors.initials: AA
authors.lastname: Geronikaki
authors.forename: John C
authors.initials: JC
authors.lastname: Dearden
authors.forename: Dmitrii
authors.initials: D
authors.lastname: Filimonov
authors.forename: Irina
authors.initials: I
authors.lastname: Galaeva
authors.forename: Taissia L
authors.initials: TL
authors.lastname: Garibova
authors.forename: Tatiana
authors.initials: T
authors.lastname: Gloriozova
authors.forename: Valentina
authors.initials: V
authors.lastname: Krajneva
authors.forename: Alexey
authors.initials: A
authors.lastname: Lagunin
authors.forename: Fliur Z
authors.initials: FZ
authors.lastname: Macaev
authors.forename: Guenadij
authors.initials: G
authors.lastname: Molodavkin
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Poroikov
authors.forename: Serghei I
authors.initials: SI
authors.lastname: Pogrebnoi
authors.forename: Felix
authors.initials: F
authors.lastname: Shepeli
authors.forename: Tatiana A
authors.initials: TA
authors.lastname: Voronina
authors.forename: Maria
authors.initials: M
authors.lastname: Tsitlakidou
authors.forename: Liudmila
authors.initials: L
authors.lastname: Vlad
mesh_terms: D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D003198:Computer Simulation; D015195:Drug Design; D008297:Male; D018697:Nootropic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D012601:Scopolamine; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D018697:Nootropic Agents; D010080:Oxazoles; D013844:Thiazoles; D012601:Scopolamine