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Weaver Lab

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

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.

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.