Design, Synthesis and Evaluation of a PLG Tripeptidomimetic Based on a Pyridine Scaffold

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 β-turn conformation that previously
has been suggested to be the bioactive conformation of PLG.