Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action, and binding site.
We have identified two chemical series of compounds acting as selective positive allosteric modulators (enhancers) of native and recombinant metabotropic glutamate 1 (mGlu1) receptors. These compounds did not directly activate mGlu1 receptors but markedly potentiated agonist-stimulated responses, increasing potency and maximum efficacy. Binding of these compounds increased the affinity of a radiolabeled glutamate-site agonist at its extracellular N-terminal binding site. Chimeric and mutated receptors were used to localize amino acids in the receptor transmembrane region critical for these enhancing properties. Finally, the compounds potentiated synaptically evoked mGlu1 receptor responses in rat brain slices. The discovery of selective positive allosteric modulators of mGlu1 receptors opens up the possibility to develop a similar class of compounds for other family 3 G protein-coupled receptors.
Knoflach
F
F
Pharma Division, Preclinical Central Nervous System Research, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland.
Mutel
V
V
Jolidon
S
S
Kew
J N
JN
Malherbe
P
P
Vieira
E
E
Wichmann
J
J
Kemp
J A
JA
D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002531:Cerebellum / Q000378:metabolism / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016318:Quisqualic Acid / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D009435:Synaptic Transmission / Q000187:drug effects; D014966:Xanthenes / Q000737:chemistry / Q000494:pharmacology*
C573813:(9H-xanthene-9-carbonyl)carbamic acid butyl ester; D002219:Carbamates; D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins; D014966:Xanthenes; D016318:Quisqualic Acid