 |
PDBsum entry 5cnj
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Signaling protein
|
PDB id
|
|
|
|
5cnj
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Synthesis and pharmacological characterization of c4-(Thiotriazolyl)-Substituted-2-Aminobicyclo[3.1.0]hexane-2,6-Dicarboxylates. Identification of (1r,2s,4r,5r,6r)-2-Amino-4-(1h-1,2,4-Triazol-3-Ylsulfanyl)bicyclo[3.1.0]hexane-2,6-Dicarboxylic acid (ly2812223), A highly potent, Functionally selective mglu2 receptor agonist.
|
|
|
Authors
|
|
J.A.Monn,
L.Prieto,
L.Taboada,
J.Hao,
M.R.Reinhard,
S.S.Henry,
C.D.Beadle,
L.Walton,
T.Man,
H.Rudyk,
B.Clark,
D.Tupper,
S.R.Baker,
C.Lamas,
C.Montero,
A.Marcos,
J.Blanco,
M.Bures,
D.K.Clawson,
S.Atwell,
F.Lu,
J.Wang,
M.Russell,
B.A.Heinz,
X.Wang,
J.H.Carter,
B.G.Getman,
J.T.Catlow,
S.Swanson,
B.G.Johnson,
D.B.Shaw,
D.L.Mckinzie.
|
|
|
Ref.
|
|
J Med Chem, 2015,
58,
7526-7548.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Identification of orthosteric mGlu2/3 receptor agonists capable of
discriminating between individual mGlu2 and mGlu3 subtypes has been highly
challenging owing to the glutamate-site sequence homology between these
proteins. Herein we detail the preparation and characterization of a series of
molecules related to (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate
1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second
messenger responses in cells expressing other recombinant human mGlu2/3
subtypes, a number of high potency and efficacy mGlu2 receptor agonists
exhibiting low potency mGlu3 partial agonist/antagonist activity were
identified. From this,
(1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic
acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with
the amino terminal domains of hmGlu2 and hmGlu3 combined with site-directed
mutation studies has clarified the underlying molecular basis of this unique
pharmacology. Evaluation of 14a in a rat model responsive to mGlu2 receptor
activation coupled with a measure of central drug disposition provides evidence
that this molecule engages and activates central mGlu2 receptors in vivo.
|
|
|
|
|
|
|
