(-)-PHCCC, a positive allosteric modulator of mGluR4: Characterization, mechanism of action, and neuroprotection

M. Maj, V. Bruno, Z. Dragic, R. Yamamoto, G. Battaglia, W. Inderbitzin, N. Stoehr, T. Stein, F. Gasparini, I. Vranesic, R. Kuhn, F. Nicoletti, P. J. Flor

Research output: Contribution to journalArticlepeer-review

Abstract

Group-III metabotropic glutamate receptors (mGluR4, -6, -7, and -8) modulate neurotoxicity of excitatory amino acids and beta-amyloid-peptide (βAP), as well as epileptic convulsions, most likely via presynaptic inhibition of glutamatergic neurotransmission. Due to the lack of subtype-selective ligands for group-III receptors, we previously utilized knock-out mice to identify mGluR4 as the primary receptor mediating neuroprotection of unselective group-III agonists such as L-AP 4 or (+)-PPG, whereas mGluR7 is critical for anticonvulsive effects. In a recent effort to find group-III subtype-selective drugs we identified (+/-)-PHCCC as a positive allosteric modulator for mGluR4. This compound increases agonist potency and markedly enhances maximum efficacy and, at higher concentrations, directly activates mGluR4 with low efficacy. All the activity of (+/-)-PHCCC resides in the (-)-enantiomer, which is inactive at mGluR2, -3, -5a, -6, -7b and -8a, but shows partial antagonist activity at mGluR1b (30% maximum antagonist efficacy). Chimeric receptor studies showed that the binding site of (-)-PHCCC is localized in the transmembrane region. Finally, (-)-PHCCC showed neuroprotection against βAP- and NMDA-toxicity in mixed cultures of mouse cortical neurons. This neuroprotection was additive to that induced by the highly efficacious mGluR1 antagonist CPCCOEt and was blocked by MSOP, a group-III mGluR antagonist. Our data provide evidence for a novel pharmacological site on mGluR4, which may be used as a target-site for therapeutics.

Original languageEnglish
Pages (from-to)895-906
Number of pages12
JournalNeuropharmacology
Volume45
Issue number7
DOIs
Publication statusPublished - Dec 2003

Keywords

  • β-amyloid toxicity
  • Excitotoxicity
  • Metabotropic glutamate receptors
  • Neuroprotection
  • Positive modulation

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

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