title: Synthesis and pharmacological characterization of 4-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates: identification of new potent and selective metabotropic glutamate 2/3 receptor agonists.
abstract: As part of our ongoing interest in identifying novel agonists acting at metabotropic glutamate (mGlu) 2/3 receptors, we have explored the effect of structural modifications of 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY354740), a potent and pharmacologically balanced mGlu2/3 receptor agonist. Incorporation of relatively small substituents (e.g., F, O) at the C4 position of this molecule resulted in additional highly potent mGlu2/3 agonists that demonstrate excellent selectivity over the other mGlu receptor subtypes, while addition of larger C4-substituents (e.g., SPh) led to a loss of agonist potency and/or the appearance of weak mGlu2/3 receptor antagonist activity. Further characterization of the α-fluoro-substituted analogue (LY459477) in vivo revealed that this molecule possesses good oral bioavailability in rats and effectively suppresses phencyclidine-evoked locomotor activity at doses that do not impair neuromuscular coordination. This molecule therefore represents a valuable new addition to the arsenal of pharmacological tools competent to investigate mGlu2/3 receptor function both in vitro and in vivo.
authors.affiliation: Discovery Chemistry Research and Technologies, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. monn@lilly.com
authors.forename: James A
authors.initials: JA
authors.lastname: Monn
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Valli
authors.forename: Steven M
authors.initials: SM
authors.lastname: Massey
authors.forename: Junliang
authors.initials: J
authors.lastname: Hao
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Reinhard
authors.forename: Mark G
authors.initials: MG
authors.lastname: Bures
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Heinz
authors.forename: Xushan
authors.initials: X
authors.lastname: Wang
authors.forename: Joan H
authors.initials: JH
authors.lastname: Carter
authors.forename: Brian G
authors.initials: BG
authors.lastname: Getman
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Stephenson
authors.forename: Marc
authors.initials: M
authors.lastname: Herin
authors.forename: John T
authors.initials: JT
authors.lastname: Catlow
authors.forename: Steven
authors.initials: S
authors.lastname: Swanson
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Johnson
authors.forename: David L
authors.initials: DL
authors.lastname: McKinzie
authors.forename: Steven S
authors.initials: SS
authors.lastname: Henry
mesh_terms: D000284:Administration, Oral; D000600:Amino Acids, Dicarboxylic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D011618:Psychotic Disorders / Q000188:drug therapy / Q000523:psychology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C581969:2-amino-4-fluorobicyclo(3.1.0)hexane-2,6-dicarboxylic acid; D000600:Amino Acids, Dicarboxylic; D014150:Antipsychotic Agents; D001643:Bridged Bicyclo Compounds; D003510:Cyclohexanes; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; C104753:eglumetad