Design and synthesis of APTCs (aminopyrrolidinetricarboxylic acids): Identification of a new group III metabotropic glutamate receptor selective agonist

A new family of mGlu receptor orthosteric ligands called APTCs was designed and synthesized using a parallel chemistry approach. Amongst 65 molecules tested on mGlu4, mGlu6 and mGlu8 subtypes, (2S,4S)-4-amino-1-[(E)-3-carboxyacryloyl]pyrrolidine-2,4-dicarboxylic acid (8a06—FP0429) has been shown to be a full mGlu4 agonist and a partial mGlu8 agonist. In addition, 8a06 was shown to be selective versus group I and II mGlu subtypes. A possible explanation for this efficacy difference is proposed by docking experiment performed with molecular model of the receptor.

Graphical abstractA new family of mGlu receptor orthosteric ligands called APTCs was designed and synthesized using parallel chemistry. Amongst them, 8a06 (FP0429) has been shown to be a full mGlu4 agonist and a partial mGlu8 agonist.Figure optionsDownload full-size imageDownload as PowerPoint slide