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.
Pharmaceuticals Division, Discovery Chemistry and Pharma Research, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland. thomas.woltering@roche.com
Thomas J
TJ
Woltering
Geo
G
Adam
Philipp
P
Huguenin
Jürgen
J
Wichmann
Sabine
S
Kolczewski
Silvia
S
Gatti
Anne
A
Bourson
James N C
JN
Kew
Grayson
G
Richards
John A
JA
Kemp
Vincent
V
Mutel
Frédéric
F
Knoflach
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