ANXIOLYTIC AND SIDE-EFFECT PROFILE OF LY354740 - A POTENT, HIGHLY SELECTIVE, ORALLY-ACTIVE AGONIST FOR GROUP-II METABOTROPIC GLUTAMATE RECEPTORS

LY354740 is a conformationally constrained analog of glutamate which i s a potent agonist for group II cAMP coupled metabotropic glutamate re ceptors (mGluRs), The discovery of this novel pharmacological agent ha s allowed the exploration of the functional consequences of activating group II mGluRs in vivo. In an effort to evaluate the clinical utilit y of LY354740 as an anxiolytic, we examined its effects in the fear po tentiated startle and elevated plus maze models of anxiety and compare d the results with the clinically prescribed anxiolytic diazepam. In t he fear potentiated startle and elevated plus maze models, both LY3547 40 and diazepam produced significant anxiolytic activity (ED50 values of 0.3 and 0.4 mg/kg p.o. for fear potentiated startle and 0.2 and 0.5 mg/kg for the elevated plus maze, respectively). The duration of phar macological effect for LY354740 in the efficacy models was 4 to 8 hr. In contrast to diazepam, acute administration of LY354740 did not prod uce sedation, cause deficits in neuromuscular coordination, interact w ith central nervous system depressants, produce memory Impairment or c hange convulsive thresholds at doses 100- to 1000-fold the efficacious doses in animal models of anxiety. Thus, LY354740 has anxiolytic acti vity in animal models that are sensitive to benzodiazepines such as di azepam. However, at anxiolytic doses in these models, LY354740 produce d none of the unwanted secondary pharmacology associated with diazepam . These data indicate a functional role for group II mGluRs in fear/an xiety responses in animals and suggest that compounds in this class ma y be beneficial in the treatment of anxiety-related disorders in human s without the side effects seen with currently prescribed medications.