Abstract：
:(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).
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Selvam C,Oueslati N,Lemasson IA,Brabet I,Rigault D,Courtiol T,Cesarini S,Triballeau N,Bertrand HO,Goudet C,Pin JP,Acher FCdoi
10.1021/jm901523tsubject
Has Abstractpub_date
2010-04-08 00:00:00pages
2797-813issue
7eissn
0022-2623issn
1520-4804journal_volume
53pub_type
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