TY - JOUR
T1 - (-)-PHCCC, a positive allosteric modulator of mGluR4
T2 - Characterization, mechanism of action, and neuroprotection
AU - Maj, M.
AU - Bruno, V.
AU - Dragic, Z.
AU - Yamamoto, R.
AU - Battaglia, G.
AU - Inderbitzin, W.
AU - Stoehr, N.
AU - Stein, T.
AU - Gasparini, F.
AU - Vranesic, I.
AU - Kuhn, R.
AU - Nicoletti, F.
AU - Flor, P. J.
PY - 2003/12
Y1 - 2003/12
N2 - 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.
AB - 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.
KW - β-amyloid toxicity
KW - Excitotoxicity
KW - Metabotropic glutamate receptors
KW - Neuroprotection
KW - Positive modulation
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U2 - 10.1016/S0028-3908(03)00271-5
DO - 10.1016/S0028-3908(03)00271-5
M3 - Article
C2 - 14573382
AN - SCOPUS:0142090782
VL - 45
SP - 895
EP - 906
JO - Neuropharmacology
JF - Neuropharmacology
SN - 0028-3908
IS - 7
ER -