title: Development of Novel, CNS Penetrant Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1 (mGlu1), Based on an N-(3-Chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide Scaffold, That Potentiate Wild Type and Mutant mGlu1 Receptors Found in Schizophrenics.
abstract: The therapeutic potential of selective mGlu1 activation is vastly unexplored relative to the other group I mGlu receptor, mGlu5; therefore, our lab has focused considerable effort toward developing mGlu1 positive allosteric modulators (PAMs) suitable as in vivo proof of concept tool compounds. Optimization of a series of mGlu1 PAMs based on an N-(3-chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide scaffold provided 17e, a potent (mGlu1 EC50 = 31.8 nM) and highly CNS penetrant (brain to plasma ratio (Kp) of 1.02) mGlu1 PAM tool compound, that potentiated not only wild-type human mGlu1 but also mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenic patients. Moreover, both electrophysiological and in vivo studies indicate the mGlu1 ago-PAMs/PAMs do not possess the same epileptiform adverse effect liability as mGlu5 ago-PAMs/PAMs and maintain temporal activity suggesting a broader therapeutic window.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Garcia-Barrantes
authors.forename: Hyekyung P
authors.initials: HP
authors.lastname: Cho
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: Frank W
authors.initials: FW
authors.lastname: Byers
authors.forename: Charles W
authors.initials: CW
authors.lastname: Locuson
authors.forename: Anna L
authors.initials: AL
authors.lastname: Blobaum
authors.forename: Zixiu
authors.initials: Z
authors.lastname: Xiang
authors.forename: Jerri M
authors.initials: JM
authors.lastname: Rook
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232-6600, United States.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D004827:Epilepsy / Q000139:chemically induced; D018755:GABA Agonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D018757:GABA Modulators / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D008968:Molecular Conformation; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*; D013329:Structure-Activity Relationship
chemical_list: D018755:GABA Agonists; D018757:GABA Modulators; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1