Design, synthesis and evaluation of a PLG tripeptidomimetic based on a pyridine scaffold
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
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.
IdentifiersURN: urn:nbn:se:umu:diva-14230DOI: doi:10.1021/jm049484qISI: 000225748500021OAI: oai:DiVA.org:umu-14230DiVA: diva2:153901