A virtual screening hit reveals new possibilities for developing group III metabotropic glutamate receptor agonists.
(R)-PCEP (3-amino-3-carboxypropyl-2'-carboxyethyl phosphinic acid, 1), a new metabotropic glutamate receptor 4 (mGlu4R) agonist, was discovered in a previously reported virtual screening. The (S)-enantiomer and a series of derivatives were synthesized and tested on recombinant mGlu4 receptors. A large number of derivatives activated this receptor but was not able to discriminate between mGlu4 and mGlu8 receptors. The most potent ones 6 and 12 displayed an EC(50) of 1.0 +/- 0.2 microM at mGlu4R. Interestingly these agonists with longer alkyl chains revealed a new binding pocket adjacent to the glutamate binding site, which is lined with residues that differ among the mGluR subtypes and that will allow the design of more selective compounds. Additionally 6 was able to activate mGlu7 receptor with an EC(50) of 43 +/- 16 microM and is thus significantly more potent than L-AP4 (EC(50) of 249 +/- 106 microM).
Selvam
Chelliah
C
Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, CNRS UMR8601, Universite Paris Descartes, 45 Rue des Saints-Peres, 75270 Paris Cedex 06, France.
Oueslati
Nadia
N
Lemasson
Isabelle A
IA
Brabet
Isabelle
I
Rigault
Delphine
D
Courtiol
Tiphanie
T
Cesarini
Sara
S
Triballeau
Nicolas
N
Bertrand
Hugues-Olivier
HO
Goudet
Cyril
C
Pin
Jean-Philippe
JP
Acher
Francine C
FC
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010721:Phosphinic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
D010721:Phosphinic Acids; D018094:Receptors, Metabotropic Glutamate