Change search
ReferencesLink to record
Permanent link

Direct link
Design, synthesis and evaluation of a PLG tripeptidomimetic based on a pyridine scaffold
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Show others and affiliations
2004 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 47, no 26, 6595-6602 p.Article in journal (Refereed) Published
Abstract [en]

A 2,3,4-substituted pyridine derivative has been identified as a potential tripeptidomimetic scaffold. The design of the scaffold was based on conformational and electrostatic comparisons with a natural tripeptide. The scaffold has been used in the synthesis of a Pro-Leu-Gly-NH2 (PLG) mimetic. The different substituents in the 2-, 3-, and 4-positions of the pyridine ring were introduced via an aromatic nucleophilic substitution reaction, a "halogen-dancing" reaction, and a Grignard coupling of a Boc-protected amino aldehyde, respectively. The synthetic route involves eight steps and provides the mimetic in 20% overall yield. The pyridine based PLG-mimetic was evaluated for its ability to enhance the maximum response of the dopamine agonist N-propylapomorphine (NPA) at human D2 receptors using a cell based assay (the R-SAT assay). The dose-response curve of the mimetic was found to exhibit a down-turn phase, similar to that of PLG. In addition, the mimetic was more potent than PLG to enhance the NPA response; the maximum response was found to be 146% at 10 nM concentration, as compared to 115% for PLG at the same concentration. Interestingly, conformational analysis by molecular modeling showed that the pyridine mimetic cannot adopt a type II -turn conformation that previously has been suggested to be the bioactive conformation of PLG.

Place, publisher, year, edition, pages
American Chemical Society , 2004. Vol. 47, no 26, 6595-6602 p.
URN: urn:nbn:se:umu:diva-14230DOI: doi:10.1021/jm049484qISI: 000225748500021OAI: diva2:153901
Available from: 2007-05-24 Created: 2007-05-24 Last updated: 2011-01-28Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Saitton, StinaBoström, DanKihlberg, Jan
By organisation
Department of Chemistry
In the same journal
Journal of Medicinal Chemistry

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 28 hits
ReferencesLink to record
Permanent link

Direct link