N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) acts through a novel site as a positive allosteric modulator of group 1 metabotropic glutamate receptors.

Chen Y, Goudet C, Pin JP, Conn PJ
Mol Pharmacol. 2008 73 (3): 909-18

PMID: 18056795 · DOI:10.1124/mol.107.040097

Recent studies suggest that a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor (mGluRs), mGluR5, termed 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU-29), potentiates mGluR5 responses by actions at a site that is overlapping with the binding site of 2-methyl-6-(phenylethynyl)pyridine (MPEP), a previously identified negative allosteric modulator of this receptor. It is interesting that a structurally distinct PAM, N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA), does not to bind to the MPEP site. We now report that CPPHA potentiates mGluR5 responses by a mechanism that is distinct from that of VU-29. VU-29- and CPPHA-induced potentiation of mGluR5 responses are blocked by a neutral ligand at the MPEP allosteric site termed 5-methyl-2-(phenylethynyl)pyridine (5MPEP). However, increasing concentrations of 5MPEP induce parallel rightward shifts in the VU-29 concentration-response curve, whereas 5MPEP inhibits CPPHA potentiation in a noncompetitive manner. Consistent with this, a mutation (A809V/mGluR5) that reduces binding of ligands to the MPEP site eliminates the effect of VU-29 but has no effect on the response to CPPHA. On the other hand, a mutation (F585I/mGluRs) that eliminates the effect of CPPHA does not alter the response to VU-29. CPPHA is also a PAM at mGluR1. It is interesting that the corresponding mutation of F585I/mGluR5 in mGluR1 (F599I/mGluR1) eliminates CPPHA's effect without altering the potentiation of a known PAM of mGluR1, (S)-2-(4-fluorophenyl)-1-(toluene-4-sulfonyl)pyrrolidine (Ro 67-7476). Likewise, another mutation (V757L/mGluR1) that abolishes potentiation of Ro 67-7476 has no effect on CPPHA. Finally, CPPHA does not displace binding of a radioligand for the mGluR1 allosteric antagonist characterized previously. Together, these data suggest that CPPHA acts at a novel allosteric site on both mGluR1 and -5 to potentiate responses to activation of these receptors.

MeSH Terms (26)

Allosteric Regulation Allosteric Site Amino Acid Sequence Amino Acid Substitution Animals Astrocytes Benzamides Calcium Cell Culture Techniques Cell Line Cells, Cultured Cerebral Cortex Cricetinae Dose-Response Relationship, Drug Humans Kidney Ligands Molecular Sequence Data Molecular Structure Protein Structure, Tertiary Radioligand Assay Rats Receptors, Metabotropic Glutamate Sequence Homology, Amino Acid Transfection Valine

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