(-)-PHCCC, a positive allosteric modulator of mGluR4: characterization, mechanism of action, and neuroprotection.
Group-III metabotropic glutamate receptors (mGluR4, -6, -7, and -8) modulate neurotoxicity of excitatory amino acids and beta-amyloid-peptide (betaAP), 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 betaAP- 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.
Maj
M
M
Novartis Institutes for BioMedical Research, Neuroscience Disease Area, WKL-125.6.08, CH-4002 Basel, Switzerland.
Bruno
V
V
Dragic
Z
Z
Yamamoto
R
R
Battaglia
G
G
Inderbitzin
W
W
Stoehr
N
N
Stein
T
T
Gasparini
F
F
Vranesic
I
I
Kuhn
R
R
Nicoletti
F
F
Flor
P J
PJ
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity; D001578:Benzopyrans / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018846:Excitatory Amino Acids / Q000633:toxicity; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000633:toxicity; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D001578:Benzopyrans; D018690:Excitatory Amino Acid Agonists; D018846:Excitatory Amino Acids; C442478:N-phenyl-7-(hydroxyimino)cyclopropa(b)chromen-1a-carboxamide; D018696:Neuroprotective Agents; D018094:Receptors, Metabotropic Glutamate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D016202:N-Methylaspartate; D000242:Cyclic AMP; D002118:Calcium; C108823:metabotropic glutamate receptor 4