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Start Over Author "Days, Emily" Topic positive allosteric modulator (pam)
2 results on '"Days, Emily"'

1. Optimization of an ether series of mGlu5 positive allosteric modulators: Molecular determinants of MPEP-site interaction crossover

Author

Manka, Jason T., Vinson, Paige N., Gregory, Karen J., Zhou, Ya, Williams, Richard, Gogi, Kiran, Days, Emily, Jadhav, Satya, Herman, Elizabeth J., Lavreysen, Hilde, Mackie, Claire, Bartolomé, José M., Macdonald, Gregor J., Steckler, Thomas, Daniels, J. Scott, Weaver, C. David, Niswender, Colleen M., Jones, Carrie K., Conn, P. Jeffrey, and Lindsley, Craig W.

Subjects
*GLUTAMATE receptors, *ALLOSTERIC regulation, *ETHERS, *AMIDES, *LABORATORY rodents, *PSYCHOSES, *CHIRALITY
Abstract

Abstract: We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu5) 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. [Copyright &y& Elsevier]

Published
2012
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2. Discovery and optimization of a novel, selective and brain penetrant M1 positive allosteric modulator (PAM): The development of ML169, an MLPCN probe

Author

Reid, Paul R., Bridges, Thomas M., Sheffler, Douglas J., Cho, Hyekyung P., Lewis, L. Michelle, Days, Emily, Daniels, J. Scott, Jones, Carrie K., Niswender, Colleen M., Weaver, C. David, Conn, P. Jeffrey, Lindsley, Craig W., and Wood, Michael R.

Subjects
*DRUG development, *ALLOSTERIC regulation, *ACETYLCHOLINE, *ALZHEIMER'S disease, *MUSCARINIC receptors, *MOLECULAR probes, *STRUCTURE-activity relationship in pharmacology
Abstract

Abstract: This Letter describes a chemical lead optimization campaign directed at VU0108370, a weak M1 PAM hit with a novel chemical scaffold from a functional HTS screen within the MLPCN. An iterative parallel synthesis approach rapidly established SAR for this series and afforded VU0405652 (ML169), a potent, selective and brain penetrant M1 PAM with an in vitro profile comparable to the prototypical M1 PAM, BQCA, but with an improved brain to plasma ratio. [Copyright &y& Elsevier]

Published
2011
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