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.
Schann
Stephan
S
Faust Pharmaceuticals, BIOPARC, Boulevard Sebastien Brant, 67400 Illkirch, France. sschann@faustpharma.com
Menet
Christel
C
Arvault
Paul
P
Mercier
Géraldine
G
Frauli
Mélanie
M
Mayer
Stanislas
S
Hubert
Nadia
N
Triballeau
Nicolas
N
Bertrand
Hugues-Olivier
HO
Acher
Francine
F
Neuville
Pascal
P
D000586:Amination; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011759:Pyrrolidines / Q000737:chemistry*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000737:chemistry / Q000145:classification / Q000378:metabolism*; D013329:Structure-Activity Relationship
D002264:Carboxylic Acids; D011759:Pyrrolidines; D018094:Receptors, Metabotropic Glutamate; C032519:pyrrolidine; D002118:Calcium