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

Jason T Manka; Paige N Vinson; Karen Joan Gregory; Ya Zhou; Richard Williams; Kiran Gogi; Emily Days; Satya Jadhav; Elizabeth J Herman; Hilde Lavreysen; Claire Mackie; Jose Bartolome; Gregor J Macdonald; Thomas Steckler; John Scott Daniels; C David Weaver; Colleen M Niswender; Carrie K Jones; Peter Jeffrey Conn; Craig W Lindsley; Shaun R Stauffer

doi:10.1016/j.bmcl.2012.08.043

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

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

Shaun R Stauffer

Drug Discovery Biology

Research output: Contribution to journal › Article › Research › peer-review

11 Citations (Scopus)

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.

Original language	English
Pages (from-to)	6481 - 6485
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	22
Issue number	20
DOIs	https://doi.org/10.1016/j.bmcl.2012.08.043
Publication status	Published - 2012

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Manka, J. T., Vinson, P. N., Gregory, K. J., Zhou, Y., Williams, R., Gogi, K., Days, E., Jadhav, S., Herman, E. J., Lavreysen, H., Mackie, C., Bartolome, J., Macdonald, G. J., Steckler, T., Daniels, J. S., Weaver, C. D., Niswender, C. M., Jones, C. K., Conn, P. J., ... Stauffer, S. R. (2012). Optimization of an ether series of mGlu5 positive allosteric modulators: molecular determinants of MPEP-site interaction crossover. Bioorganic and Medicinal Chemistry Letters, 22(20), 6481 - 6485. https://doi.org/10.1016/j.bmcl.2012.08.043

@article{e50d7f3b777f41a49487978bf394e61c,

title = "Optimization of an ether series of mGlu5 positive allosteric modulators: molecular determinants of MPEP-site interaction crossover",

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.",

author = "Manka, \{Jason T\} and Vinson, \{Paige N\} and Gregory, \{Karen Joan\} and Ya Zhou and Richard Williams and Kiran Gogi and Emily Days and Satya Jadhav and Herman, \{Elizabeth J\} and Hilde Lavreysen and Claire Mackie and Jose Bartolome and Macdonald, \{Gregor J\} and Thomas Steckler and Daniels, \{John Scott\} and Weaver, \{C David\} and Niswender, \{Colleen M\} and Jones, \{Carrie K\} and Conn, \{Peter Jeffrey\} and Lindsley, \{Craig W\} and Stauffer, \{Shaun R\}",

year = "2012",

doi = "10.1016/j.bmcl.2012.08.043",

language = "English",

volume = "22",

pages = "6481 -- 6485",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier",

number = "20",

}

Manka, JT, Vinson, PN, Gregory, KJ, Zhou, Y, Williams, R, Gogi, K, Days, E, Jadhav, S, Herman, EJ, Lavreysen, H, Mackie, C, Bartolome, J, Macdonald, GJ, Steckler, T, Daniels, JS, Weaver, CD, Niswender, CM, Jones, CK, Conn, PJ, Lindsley, CW & Stauffer, SR 2012, 'Optimization of an ether series of mGlu5 positive allosteric modulators: molecular determinants of MPEP-site interaction crossover', Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 20, pp. 6481 - 6485. https://doi.org/10.1016/j.bmcl.2012.08.043

TY - JOUR

T1 - Optimization of an ether series of mGlu5 positive allosteric modulators: molecular determinants of MPEP-site interaction crossover

AU - Manka, Jason T

AU - Vinson, Paige N

AU - Gregory, Karen Joan

AU - Zhou, Ya

AU - Williams, Richard

AU - Gogi, Kiran

AU - Days, Emily

AU - Jadhav, Satya

AU - Herman, Elizabeth J

AU - Lavreysen, Hilde

AU - Mackie, Claire

AU - Bartolome, Jose

AU - Macdonald, Gregor J

AU - Steckler, Thomas

AU - Daniels, John Scott

AU - Weaver, C David

AU - Niswender, Colleen M

AU - Jones, Carrie K

AU - Conn, Peter Jeffrey

AU - Lindsley, Craig W

AU - Stauffer, Shaun R

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

UR - http://www.sciencedirect.com/science/article/pii/S0960894X12010438

U2 - 10.1016/j.bmcl.2012.08.043

DO - 10.1016/j.bmcl.2012.08.043

M3 - Article

SN - 0960-894X

VL - 22

SP - 6481

EP - 6485

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 20

ER -

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

Abstract

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