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Synthesis and evaluation of novel pyridine based PLG tripeptidomimetics
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Science and Technology, Chemistry.
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2008 (English)In: Organic & Biomolecular Chemistry, Vol. 6, no 9, 1647-54 p.Article in journal (Refereed) Published
Abstract [en]

Analogues of the pyridine based PLG (Pro-Leu-Gly-NH2) peptidomimetic 1 were synthesized and evaluated as dopamine modulating agents. Modifications in the position corresponding to the leucine side chain in PLG afforded derivatives 2, 3 and 4, substituted with H, Me and Bn instead of the isobutyl group, respectively. Changes in the proline residue produced derivative 5, substituted with a symmetrical piperidine ring instead of the pyrrolidine ring and 6, in which the pyrrolidine ring is connected to the pyridine ring via a hydroxymethyl group instead of a keto function. The peptidomimetics were tested for their ability to enhance the maximal effect of N-propylapomorphine (NPA) at dopamine D2 receptors in the functional cell-based R-SAT assay. Compounds 2, 3, and 4, produced a statistically significant increase in the maximal NPA response at 10 nM (117 ± 6%, 118 ± 6%, and 116 ± 3%, respectively), which is similar to the effect of PLG in this assay, whereas 5 was able to potentiate the response to a similar extent at 1 nM concentration (115 ± 5%). All derivatives produced a bell-shaped dose-response curve and none of the compounds were active at the D2 receptor alone, which indicates that the mechanism behind the activity of both the pyridine based mimetics 1-6 and PLG is the same. Interestingly, L-Pro-D-Leu-Gly-NH2 was found to be more potent than PLG and produced a 119 ± 1% increase in the NPA response at 1 nM.

Place, publisher, year, edition, pages
2008. Vol. 6, no 9, 1647-54 p.
URN: urn:nbn:se:umu:diva-9678DOI: doi:10.1039/b718058fOAI: diva2:149349
Available from: 2008-05-19 Created: 2008-05-19 Last updated: 2011-01-10Bibliographically approved

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Kihlberg, Jan
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