title: Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: in vitro characterization of agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (LY404039).
abstract: Group II metabotropic glutamate (mGlu) receptor agonists, including (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740) and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), have demonstrated efficacy in animal models of anxiety and schizophrenia, and LY354740 decreased anxiety in human subjects. Herein, we report the in vitro pharmacological profile and pharmacokinetic properties of another potent, selective, and structurally novel mGlu2/3 receptor agonist, (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039) and provide comparisons with LY354740. Similar to LY354740, LY404039 is a nanomolar potent agonist at recombinant human mGlu2 and mGlu3 receptors (K(i) = 149 and 92, respectively) and in rat neurons expressing native mGlu2/3 receptors (Ki = 88). LY404039 is highly selective for mGlu2/3 receptors, showing more than 100-fold selectivity for these receptors, versus ionotropic glutamate receptors, glutamate transporters, and other receptors targeted by known anxiolytic and antipsychotic medications. Functionally, LY404039 potently inhibited forskolin-stimulated cAMP formation in cells expressing human mGlu2 and mGlu3 receptors. Electrophysiological studies indicated that LY404039 suppressed electrically evoked excitatory activity in the striatum, and serotonin-induced l-glutamate release in the prefrontal cortex; effects reversed by LY341495. These characteristics suggest LY404039 modulates glutamatergic activity in limbic and forebrain areas relevant to psychiatric disorders; and that, similar to LY354740, it works through a mechanism that may be devoid of negative side effects associated with current antipsychotics and anxiolytics. Interestingly, despite the slightly lower potency (approximately 2-5-fold) of LY404039 versus LY354740 in binding, functional, and electrophysiological assays, LY404039 demonstrated higher plasma exposure and better oral bioavailability in pharmacokinetic experiments. Collectively, the current data indicate that LY404039 may be valuable in the treatment of neuropsychiatric disorders, including anxiety and psychosis.
authors.affiliation: Neuroscience Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, DC0510, Indianapolis, IN 46285, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Rorick-Kehn
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Johnson
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Burkey
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Wright
authors.forename: David O
authors.initials: DO
authors.lastname: Calligaro
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Marek
authors.forename: Eric S
authors.initials: ES
authors.lastname: Nisenbaum
authors.forename: John T
authors.initials: JT
authors.lastname: Catlow
authors.forename: Ann E
authors.initials: AE
authors.lastname: Kingston
authors.forename: Deborah D
authors.initials: DD
authors.lastname: Giera
authors.forename: Marc F
authors.initials: MF
authors.lastname: Herin
authors.forename: James A
authors.initials: JA
authors.lastname: Monn
authors.forename: David L
authors.initials: DL
authors.lastname: McKinzie
authors.forename: Darryle D
authors.initials: DD
authors.lastname: Schoepp
mesh_terms: D000818:Animals; D001665:Binding Sites; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D003499:Cyclic S-Oxides / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004558:Electric Stimulation; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008297:Male; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology
chemical_list: C517803:4-aminho-2-thiabicyclo(3.1.0)hexane-4,6-dicarboxylic acid; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003499:Cyclic S-Oxides; D018690:Excitatory Amino Acid Agonists; D010716:Phosphatidylinositols; D018094:Receptors, Metabotropic Glutamate; D012702:Serotonin Antagonists; D005576:Colforsin; D012701:Serotonin; D000242:Cyclic AMP; C104753:eglumetad