title: Improved bioavailability of the mGlu2/3 receptor agonist LY354740 using a prodrug strategy: in vivo pharmacology of LY544344.
abstract: Numerous studies have indicated that selective agonists of group II metabotropic glutamate (mGlu) receptors, such as LY354740 [(1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate] and LY379268 [(-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate], may be useful in the treatment of many psychiatric disorders, including psychosis, anxiety, and drug withdrawal. Although animal and human studies demonstrate potential therapeutic utility, poor oral bioavailability is a limiting factor in the clinical development of these compounds. Therefore, a novel prodrug approach is being pursued to increase exposure levels of active compound after oral administration. Here, we demonstrate a 10-fold increase in brain, plasma, and cerebrospinal fluid levels of LY354740 after oral prodrug administration. Furthermore, we compare the oral efficacy of the mGlu2/3 receptor agonist LY354740 and its prodrug LY544344 [(1S,2S,5R,6S)-2-[(2'S)-(2'-amino)propionyl]aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride] in rodent models of psychosis and anxiety. Phencyclidine (PCP)-induced hyperlocomotion was dose dependently inhibited in rats receiving oral administration of 30 or 100 mg/kg LY544344, whereas LY354740 did not significantly reverse PCP-mediated behaviors at doses up to 100 mg/kg. Orally administered LY544344 (30 mg/kg) and subcutaneously administered LY354740 (10 mg/kg) attenuated stress-induced hyperthermia in DBA/2 mice, with the prodrug producing anxiolytic effects at lower oral doses than the parent compound. Although oral administration of LY354740 did not significantly affect fear-induced suppression of operant responding in rats, subcutaneously administered LY354740 (10 or 20 mg/kg) and orally administered LY544344 (10 or 30 mg/kg) produced significant anxiolytic effects in this model. The present data confirm that mGlu2/3 receptor agonists produce antipsychotic and anxiolytic effects in animal behavioral models and demonstrate that oral bioavailability of LY354740 was substantially increased using a prodrug strategy.
authors.affiliation: Neuroscience Discovery Research Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Rorick-Kehn
authors.forename: Everett J
authors.initials: EJ
authors.lastname: Perkins
authors.forename: Karen M
authors.initials: KM
authors.lastname: Knitowski
authors.forename: John C
authors.initials: JC
authors.lastname: Hart
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Johnson
authors.forename: Darryle D
authors.initials: DD
authors.lastname: Schoepp
authors.forename: David L
authors.initials: DL
authors.lastname: McKinzie
mesh_terms: D000284:Administration, Oral; D000409:Alanine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001682:Biological Availability; D001831:Body Temperature / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D013312:Stress, Physiological / Q000503:physiopathology; D013997:Time Factors
chemical_list: C503966:2-((2'-amino)propionyl)aminobicyclo(3.1.0)hexane-2,6-dicarboxylic acid; D001643:Bridged Bicyclo Compounds; D011355:Prodrugs; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D000409:Alanine; C104753:eglumetad