Design of new cognition enhancers: from computer prediction to synthesis and biological evaluation.
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.
Geronikaki
Athina A
AA
School of Pharmacy, Department of Pharmaceutical Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece. geronik@pharm.auth.gr
Dearden
John C
JC
Filimonov
Dmitrii
D
Galaeva
Irina
I
Garibova
Taissia L
TL
Gloriozova
Tatiana
T
Krajneva
Valentina
V
Lagunin
Alexey
A
Macaev
Fliur Z
FZ
Molodavkin
Guenadij
G
Poroikov
Vladimir V
VV
Pogrebnoi
Serghei I
SI
Shepeli
Felix
F
Voronina
Tatiana A
TA
Tsitlakidou
Maria
M
Vlad
Liudmila
L
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
D018697:Nootropic Agents; D010080:Oxazoles; D013844:Thiazoles; D012601:Scopolamine