(2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-methylcyclopropyl) glycine is a potent and selective metabotropic group 2 receptor agonist with anxiolytic properties.
The asymmetric synthesis and biological activity of (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-methylcyclopropyl) glycine 7 and its epimer at the C3' center 6 are described. Compound 7 is a highly potent and selective agonist for group 2 metabotropric glutamate receptors (mGluRs). It is also systemically 4 orders of magnitude more active in the fear-potentiated startle model of anxiety in rats than the rigid constrained bicyclic system LY354740. Therefore, we have shown that high molecular complexity of conformationally constrained bicyclic systems is not a requirement to achieve highly selective and potent group 2 mGluRs agonists.
Collado
Iván
I
Lilly, SA. Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain. collado_ivan@lilly.com
Pedregal
Concepción
C
Mazón
Angel
A
Espinosa
Juan Félix
JF
Blanco-Urgoiti
Jaime
J
Schoepp
Darryle D
DD
Wright
Rebecca A
RA
Johnson
Bryan G
BG
Kingston
Ann E
AE
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D013216:Reflex, Startle / Q000187:drug effects; D013237:Stereoisomerism
C464665:2-(2'-carboxy-3'-methylcyclopropyl)glycine; D014151:Anti-Anxiety Agents; D001643:Bridged Bicyclo Compounds; D003521:Cyclopropanes; D008024:Ligands; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C104753:eglumetad; D005998:Glycine