Received for publication July 5, 2005.
Revised October 11, 2005.
Accepted for publication October 12, 2005.

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 and LY379268, 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 in order to increase exposure levels of active compound following oral administration. Here, we demonstrate a 10-fold increase in brain, plasma, and CSF levels of LY354740 following oral prodrug administration. Further, we compare the oral efficacy of the mGlu2/3 receptor agonist LY354740 and its prodrug (LY544344) 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.

Key words: anxiety, conditioned emotional response, locomotor activity, metabotropic glutamate (mGlu) receptors, psychosis, stress-induced hyperthermia

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