Improved bioavailability of the mGlu2/3 receptor agonist LY354740 using a prodrug strategy: In vivo pharmacology of LY544344

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- 4aminobicyclo[ 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.