Organic & Biomolecular Chemistry 2008-05-07

Synthesis and evaluation of novel pyridine based PLG tripeptidomimetics.

Stina Saitton, Andria L Del Tredici, Maria Saxin, Tobias Stenström, Jan Kihlberg, Kristina Luthman

Index: Org. Biomol. Chem. 6(9) , 1647-54, (2008)

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Abstract

Analogues of the pyridine based PLG (Pro-Leu-Gly-NH(2)) peptidomimetic were synthesized and evaluated as dopamine modulating agents. Modifications in the position corresponding to the leucine side chain in PLG afforded derivatives , and , substituted with H, Me and Bn instead of the isobutyl group, respectively. Changes in the proline residue produced derivative , substituted with a symmetrical piperidine ring instead of the pyrrolidine ring and , 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 , , and , 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 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 and PLG is the same. Interestingly, l-Pro-d-Leu-Gly-NH(2) was found to be more potent than PLG and produced a 119 +/- 1% increase in the NPA response at 1 nM.