Document Detail


Creatinyl amino acids: new hybrid compounds with neuroprotective activity.
MedLine Citation:
PMID:  21644247     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Prolonged oral creatine administration resulted in remarkable neuroprotection in experimental models of brain stroke. However, because of its polar nature creatine has poor ability to penetrate the blood-brain barrier (BBB) without specific creatine transporter (CRT). Thus, synthesis of hydrophobic derivatives capable of crossing the BBB by alternative pathway is of great importance for the treatment of acute and chronic neurological diseases including stroke, traumatic brain injury and hereditary CRT deficiency. Here we describe synthesis of new hybrid compounds-creatinyl amino acids, their neuroprotective activity in vivo and stability to degradation in different media. The title compounds were synthesized by guanidinylation of corresponding sarcosyl peptides or direct creatine attachment using isobutyl chloroformate method. Addition of lipophilic counterion (p-toluenesulfonate) ensures efficient creatine dissolution in DMF with simultaneous protection of guanidino group towards intramolecular cyclization. It excludes the application of expensive guanidinylating reagents, permits to simplify synthetic procedure and adapt it to large-scale production. The biological activity of creatinyl amino acids was tested in vivo on ischemic stroke and NaNO(2) -induced hypoxia models. One of the most effective compounds-creatinyl-glycine ethyl ester increases life span of experimental animals more than two times in hypoxia model and has neuroprotective action in brain stroke model when applied both before and after ischemia. These data evidenced that creatinyl amino acids can represent promising candidates for the development of new drugs useful in stroke treatment.
Authors:
Sergey Burov; Maria Leko; Marina Dorosh; Anatoliy Dobrodumov; Olga Veselkina
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Publication Detail:
Type:  Journal Article     Date:  2011-06-06
Journal Detail:
Title:  Journal of peptide science : an official publication of the European Peptide Society     Volume:  17     ISSN:  1099-1387     ISO Abbreviation:  J. Pept. Sci.     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-08-08     Completed Date:  2011-12-06     Revised Date:  2011-12-16    
Medline Journal Info:
Nlm Unique ID:  9506309     Medline TA:  J Pept Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  620-6     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.
Affiliation:
Institute of Macromolecular Compounds RAS, St. Petersburg, Russia. burov@hq.macro.ru
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MeSH Terms
Descriptor/Qualifier:
Amino Acids / chemistry*,  metabolism,  therapeutic use
Animals
Blood-Brain Barrier / metabolism
Creatine / chemistry*,  metabolism,  therapeutic use
Male
Molecular Structure
Neuroprotective Agents / chemistry*,  metabolism,  therapeutic use
Rats
Rats, Wistar
Stroke / drug therapy
Chemical
Reg. No./Substance:
0/Amino Acids; 0/Neuroprotective Agents; 57-00-1/Creatine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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