Discovery of a novel chemical class of mGlu5 allosteric ligands with distinct modes of pharmacology

Alexis Hammond, Alice L. Rodriguez, Steven D. Townsend, Colleen M. Niswender, Karen J. Gregory, Craig W. Lindsley, P. Jeffrey Conn

Research output: Contribution to journalArticle

Abstract

We previously discovered a positive allosteric modulator (PAM) of the metabotropic glutamate receptor subtype 5 (mGlu5) termed 4 N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl} -2-hydroxybenzamide (CPPHA) that elicits receptor activation through a novel allosteric site on mGlu5, distinct from the classical mGlu 5 negative allosteric modulator (NAM) MPEP allosteric site. However, a shallow structure-activity relationship (SAR), poor physiochemical properties, and weak PAM activity at rat mGlu5 limited the utility of CPPHA to explore allosteric activation of mGlu5 at a non-MPEP site. Thus, we performed a functional high-throughput screen (HTS) and identified a novel mGlu5 PAM benzamide scaffold, exemplified by VU0001850 (EC 50 = 1.3 μM, 106% Glumax) and VU0040237 (EC 50 = 350 nM, 84% Glu Max). An iterative parallel synthesis approach delivered 22 analogues, optimized mGlu5 PAM activity to afford VU0357121 (EC50 = 33 nM, 92% Glumax), and also revealed the first non-MPEP site neutral allosteric ligand (VU0365396). Like CPPHA, PAMs within this class do not appear to bind at the MPEP allosteric site based on radioligand binding studies. Moreover, mutagenesis studies indicate that VU0357121 and related analogues bind to a yet uncharacterized allosteric site on mGlu5, distinct from CPPHA, yet share a functional interaction with the MPEP site.

Original languageEnglish (US)
Pages (from-to)702-716
Number of pages15
JournalACS Chemical Neuroscience
Volume1
Issue number10
DOIs
StatePublished - Oct 20 2010
Externally publishedYes

Fingerprint

Allosteric Site
Modulators
Pharmacology
Ligands
Chemical activation
Metabotropic Glutamate 5 Receptor
Pulse amplitude modulation
Mutagenesis
Metabotropic Glutamate Receptors
Structure-Activity Relationship
Scaffolds
Rats
Throughput

Keywords

  • allosteric
  • glutamate
  • metabotropic
  • mGlu
  • potentiator

ASJC Scopus subject areas

  • Physiology
  • Biochemistry
  • Cognitive Neuroscience
  • Cell Biology

Cite this

Hammond, A., Rodriguez, A. L., Townsend, S. D., Niswender, C. M., Gregory, K. J., Lindsley, C. W., & Conn, P. J. (2010). Discovery of a novel chemical class of mGlu5 allosteric ligands with distinct modes of pharmacology. ACS Chemical Neuroscience, 1(10), 702-716. https://doi.org/10.1021/cn100051m

Discovery of a novel chemical class of mGlu5 allosteric ligands with distinct modes of pharmacology. / Hammond, Alexis; Rodriguez, Alice L.; Townsend, Steven D.; Niswender, Colleen M.; Gregory, Karen J.; Lindsley, Craig W.; Conn, P. Jeffrey.

In: ACS Chemical Neuroscience, Vol. 1, No. 10, 20.10.2010, p. 702-716.

Research output: Contribution to journalArticle

Hammond, A, Rodriguez, AL, Townsend, SD, Niswender, CM, Gregory, KJ, Lindsley, CW & Conn, PJ 2010, 'Discovery of a novel chemical class of mGlu5 allosteric ligands with distinct modes of pharmacology', ACS Chemical Neuroscience, vol. 1, no. 10, pp. 702-716. https://doi.org/10.1021/cn100051m
Hammond, Alexis ; Rodriguez, Alice L. ; Townsend, Steven D. ; Niswender, Colleen M. ; Gregory, Karen J. ; Lindsley, Craig W. ; Conn, P. Jeffrey. / Discovery of a novel chemical class of mGlu5 allosteric ligands with distinct modes of pharmacology. In: ACS Chemical Neuroscience. 2010 ; Vol. 1, No. 10. pp. 702-716.
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