Synthesis and metabotropic glutamate receptor activity of S-oxidized variants of (-)-4-amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate: identification of potent, selective, and orally bioavailable agonists for mGlu2/3 receptors.
(-)-4-Amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate (LY389795, (-)-3) is a highly potent and selective agonist of metabotropic glutamate receptors 2 (mGlu2) and 3 (mGlu3). As part of our ongoing research program, we have prepared S-oxidized variants of (-)-3, compounds (-)-10, (+)-11 (LY404040), and (-)-12 (LY404039). Each of these chiral heterobicyclic amino acids displaced specific binding of the mGlu2/3 receptor antagonist 3H-2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (3H-LY341495) from membranes expressing recombinant human mGlu2 or mGlu3 and acted as potent agonists in cells expressing these receptor subtypes. Docking of the most potent of these derivatives, (+)-11, to mGlu2 revealed the possibility of an additional H-bond interaction between the sulfoxide oxygen of (+)-11 with tyrosine residue Y236. Pharmacokinetic analysis of mGlu active enantiomers (+)-11 and (-)-12 in rats showed each to be well absorbed following oral administration. Consistent with their mGlu2/3 agonist potency and pharmacokinetic properties, both (+)-11 and (-)-12 blocked phencyclidine-evoked ambulations in a dose-dependent manner, indicating their potential as nonclassical antipsychotic agents.
Monn
James A
JA
Neuroscience Research Division, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. monn@lilly.com
Massey
Steven M
SM
Valli
Matthew J
MJ
Henry
Steven S
SS
Stephenson
Gregory A
GA
Bures
Mark
M
Hérin
Marc
M
Catlow
John
J
Giera
Deborah
D
Wright
Rebecca A
RA
Johnson
Bryan G
BG
Andis
Sherri L
SL
Kingston
Ann
A
Schoepp
Darryle D
DD
D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D011916:Rats, Inbred F344; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C517803:4-aminho-2-thiabicyclo(3.1.0)hexane-4,6-dicarboxylic acid; D014150:Antipsychotic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003499:Cyclic S-Oxides; D008024:Ligands; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3