Methyl substitution of 2-aminobicyclo[3.1.0]hexane 2,6-dicarboxylate (LY354740) determines functional activity at metabotropic glutamate receptors: identification of a subtype selective mGlu2 receptor agonist.
LY354740 (1) is a highly potent and selective agonist of metabotropic glutamate (mGlu) receptors 2 and 3. In the present study, we have prepared C3- and C4-methyl-substituted variants of rac-1, compounds 5, 9, and 13. Each of these racemic methyl-substituted analogues displaced specific binding of the mGlu2/3 receptor antagonist (3)H-2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid ((3)H-LY341495) from membranes expressing mGlu2 or mGlu3 receptor subtypes. Evaluation of the functional effects of this series on second messenger responses in cells expressing human mGlu2 or mGlu3 receptors revealed C3beta-methyl analogue 5 to possess antagonist properties at both mGlu2 and mGlu3 receptors while C4beta-methyl analogue 9 acts as a full agonist at each of these targets. Unexpectedly, we found that incorporation of a methyl substituent at the C4alpha-position as in analogue 13 results in a mixed mGlu2 agonist/mGlu3 antagonist pharmacological profile. All of the mGlu2 agonist and mGlu3 antagonist activity of rac-13 was found to reside in its resolved (+)-isomer.
Dominguez
Carmen
C
Discovery Chemistry and Neuroscience Research Divisions, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Prieto
Lourdes
L
Valli
Matthew J
MJ
Massey
Steven M
SM
Bures
Mark
M
Wright
Rebecca A
RA
Johnson
Bryan G
BG
Andis
Sherri L
SL
Kingston
Ann
A
Schoepp
Darryle D
DD
Monn
James A
JA
D000818:Animals; D001667:Binding, Competitive; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D011869:Radioligand Assay; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000502:physiology; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001643:Bridged Bicyclo Compounds; D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D000242:Cyclic AMP; C104753:eglumetad