Optimization of an ether series of mGlu5 positive allosteric modulators: molecular determinants of MPEP-site interaction crossover.
AUTHORS
Manka
JTJason T ,
Vinson
PN Paige N ,
Gregory
KJ Karen J ,
Zhou
Y Ya ,
Williams
R Richard ,
Gogi
K Kiran ,
Days
E Emily ,
Jadhav
S Satya ,
Herman
EJ Elizabeth J ,
Lavreysen
H Hilde ,
Mackie
C Claire ,
Bartolomé
JM José M ,
Macdonald
GJ Gregor J ,
Steckler
T Thomas ,
Daniels
JS J Scott ,
Weaver
CD C David ,
Niswender
CM Colleen M ,
Jones
CK Carrie K ,
Conn
PJ P Jeffrey ,
Lindsley
CW Craig W ,
Stauffer
SR Shaun R .
Bioorganic & medicinal chemistry letters. 2012 10 15; 22(20).
6481-5
- PMID: 22981332[PubMed].
- PMCID: PMC3755010.
- NIHMSID: NIHMS498112
ABSTRACT
We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on a simple acyclic ether series. Modifications led to a gain of MPEP site interaction through incorporation of a chiral amide in conjunction with a nicotinamide core. A highly potent PAM, 8v (VU0404251), was shown to be efficacious in a rodent model of psychosis. These studies suggest that potent PAMs within topologically similar chemotypes can be developed to preferentially interact or not interact with the MPEP allosteric binding site.