Discovery of a potent, selective and orally active in vivo mGlu4 positive allosteric modulator

Corey R. Hopkins; Darren W. Engers; Colleen M. Niswender; Carrie K. Jones; Eric Dawson; C. David Weaver; J. Scott Daniels; P. Jeffrey Conn; Craig W. Lindsley

Discovery of a potent, selective and orally active in vivo mGlu₄ positive allosteric modulator

Review

In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010.

2010 Oct 29 [updated 2013 Mar 14].

Authors

Corey R. Hopkins¹, Darren W. Engers¹, Colleen M. Niswender², Carrie K. Jones², Eric Dawson¹, C. David Weaver³, J. Scott Daniels², P. Jeffrey Conn², Craig W. Lindsley¹

Affiliations

¹ Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, Nashville, TN 37232
² Vanderbilt University, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, TN 37232
³ Vanderbilt Screening Center for GPCRs, Ion Channels, and Transporters (MLSCN), Nashville, TN 37232

PMID: 23762961
Bookshelf ID: NBK143194

Excerpt

ML182 was identified through a medicinal chemistry campaign that was designed to improve the in vivo characteristics of ML128. ML182 is a potent and novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 4 (mGlu₄) – hEC₅₀ = 291 nM; rEC₅₀ = 376 nM. ML182 shows excellent in vitro and in vivo pharmacokinetic characteristics and was shown to be active in an anti-Parkinsonian animal model after oral dosing (haloperidol-induced catalepsy). This will find utility in the Parkinson’s and mGlu community as a novel, selective and potent PAM of mGlu₄.

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