title: Chemical modulation of mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenics.
abstract: Schizophrenia is a complex and highly heterogeneous psychiatric disorder whose precise etiology remains elusive. While genome-wide association studies (GWAS) have identified risk genes, they have failed to determine if rare coding single nucleotide polymorphisms (nsSNPs) contribute in schizophrenia. Recently, two independent studies identified 12 rare, deleterious nsSNPS in the GRM1 gene, which encodes the metabotropic glutamate receptor subtype 1 (mGlu1), in schizophrenic patients. Here, we generated stable cell lines expressing the mGlu1 mutant receptors and assessed their pharmacology. Using both the endogenous agonist glutamate and the synthetic agonist DHPG, we found that several of the mutant mGlu1 receptors displayed a loss of function that was not due to a loss in plasma membrane expression. Due to a lack of mGlu1 positive allosteric modulators (PAM) tool compounds active at human mGlu1, we optimized a known mGlu4 PAM/mGlu1 NAM chemotype into a series of potent and selective mGlu1 PAMs by virtue of a double "molecular switch". Employing mGlu1 PAMs from multiple chemotypes, we demonstrate that the mutant receptors can be potentiated by small molecules and in some cases efficacy restored to that comparable to wild type mGlu1 receptors, suggesting deficits in patients with schizophrenia due to these mutations may be amenable to intervention with an mGlu1 PAM. However, in wild type animals, mGlu1 negative allosteric modulators (NAMs) are efficacious in classic models predictive of antipsychotic activity, whereas we show that mGlu1 PAMs have no effect to slight potentiation in these models. These data further highlight the heterogeneity of schizophrenia and the critical role of patient selection strategies in psychiatric clinical trials to match genotype with therapeutic mechanism.
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, ‡Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232 United States.
authors.forename: Hyekyung P
authors.initials: HP
authors.lastname: Cho
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Garcia-Barrantes
authors.forename: John T
authors.initials: JT
authors.lastname: Brogan
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: Alice L
authors.initials: AL
authors.lastname: Rodriguez
authors.forename: Daryl F
authors.initials: DF
authors.lastname: Venable
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morrison
authors.forename: Michael
authors.initials: M
authors.lastname: Bubser
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002853:Chromatography, Liquid; D055106:Genome-Wide Association Study; D018698:Glutamic Acid / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008124:Locomotion; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry* / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D018094:Receptors, Metabotropic Glutamate; D054852:Small Molecule Libraries; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; D002118:Calcium