Document Detail


Development of 2'-substituted (2S,1'R,2'S)-2-(carboxycyclopropyl)glycine analogues as potent N-methyl-d-aspartic acid receptor agonists.
MedLine Citation:
PMID:  23614571     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A series of 2'-substituted analogues of the selective NMDA receptor ligand (2S,1'R,2'S)-2-(carboxycyclopropyl)glycine ((S)-CCG-IV) have been designed, synthesized, and pharmacologically characterized. The design was based on a docking study hypothesizing that substituents in the 2'-position would protrude into a region where differences among the NMDA receptor GluN2 subunits exist. Various synthetic routes were explored, and two different routes provided a series of alkyl-substituted analogues. Pharmacological characterization revealed that these compounds are NMDA receptor agonists and that potency decreases with increasing size of the alkyl groups. Variations in agonist activity are observed at the different recombinant NMDA receptor subtypes. This study demonstrates that it is possible to introduce substituents in the 2'-position of (S)-CCG-IV while maintaining agonist activity and that variation among NMDA receptor subtypes may be achieved by probing this region of the receptor.
Authors:
Rune Risgaard; Simon D Nielsen; Kasper B Hansen; Christina M Jensen; Birgitte Nielsen; Stephen F Traynelis; Rasmus P Clausen
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural     Date:  2013-05-09
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  56     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-05-23     Completed Date:  2013-07-23     Revised Date:  2014-05-27    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4071-81     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amino Acids, Dicarboxylic / chemical synthesis*,  pharmacology*
Animals
Chromatography, Thin Layer
Cyclopropanes / chemistry
Drug Design
Excitatory Amino Acid Agonists / chemical synthesis*,  pharmacology*
Indicators and Reagents
Oocytes / drug effects
Patch-Clamp Techniques
Rats
Receptors, N-Methyl-D-Aspartate / agonists*
Solvents
Spectrophotometry, Ultraviolet
Synaptosomes / drug effects,  metabolism
Xenopus
Grant Support
ID/Acronym/Agency:
NS036654/NS/NINDS NIH HHS; NS065371/NS/NINDS NIH HHS; R37 NS036654/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Amino Acids, Dicarboxylic; 0/Cyclopropanes; 0/Excitatory Amino Acid Agonists; 0/Indicators and Reagents; 0/Receptors, N-Methyl-D-Aspartate; 0/Solvents; 22255-17-0/(alpha-carboxycyclopropyl)glycine; 99TB643425/cyclopropane
Comments/Corrections

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


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