Asymmetric synthesis and receptor pharmacology of the group II mGlu receptor ligand (1S,2R,3R,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid-HYDIA.
The asymmetric synthesis and receptor pharmacology of (1S,2R,3R,5R,6S)-2-amino-3-Hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (+)-9 (HYDIA) and a few of its O-alkylated derivatives are described. The key step of the synthesis utilizes Sharpless' asymmetric dihydroxylation (AD-beta) for the kinetic resolution of a bicyclic racemic precursor olefin. In contrast to the bicyclic glutamate analogue LY354740, which is a potent and selective agonist for the group II metabotropic glutamate receptors (mGluRs), these new conformationally restricted and also hydroxylated or alkoxylated glutamate analogues are potent and selective antagonists for the group II mGluRs.
Woltering
Thomas J
TJ
Pharmaceuticals Division, Discovery Chemistry and Pharma Research, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland. thomas.woltering@roche.com
Adam
Geo
G
Huguenin
Philipp
P
Wichmann
Jürgen
J
Kolczewski
Sabine
S
Gatti
Silvia
S
Bourson
Anne
A
Kew
James N C
JN
Richards
Grayson
G
Kemp
John A
JA
Mutel
Vincent
V
Knoflach
Frédéric
F
D000478:Alkylation; D000818:Animals; D001667:Binding, Competitive; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D018698:Glutamic Acid / Q000737:chemistry / Q000494:pharmacology; D006900:Hydroxylation; D008024:Ligands; D051379:Mice; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C544072:2-amino-3-hydroxybicyclo(3.1.0)hexane-2,6-dicarboxylic acid; D001643:Bridged Bicyclo Compounds; D018690:Excitatory Amino Acid Agonists; D008024:Ligands; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D018698:Glutamic Acid; C104753:eglumetad