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Vol. 284, Issue 2, 651-660, February 1998
Toxicology Research (D.R.H., J.P.T., M.J.K.) and
Neuroscience
Research Division (J.A.M., D.D.S.), Eli Lilly and Company, Greenfield,
Indiana
LY354740 is a conformationally constrained analog of glutamate which is
a potent agonist for group II cAMP coupled metabotropic glutamate
receptors (mGluRs). The discovery of this novel pharmacological agent
has allowed the exploration of the functional consequences of
activating group II mGluRs in vivo. In an effort to evaluate the clinical utility of LY354740 as an anxiolytic, we examined its
effects in the fear potentiated startle and elevated plus maze models
of anxiety and compared the results with the clinically prescribed
anxiolytic diazepam. In the fear potentiated startle and elevated plus
maze models, both LY354740 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 pharmacological effect for LY354740 in
the efficacy models was 4 to 8 hr. In contrast to diazepam, acute
administration of LY354740 did not produce sedation, cause deficits in
neuromuscular coordination, interact with central nervous system
depressants, produce memory impairment or change convulsive thresholds
at doses 100- to 1000-fold the efficacious doses in animal models of
anxiety. Thus, LY354740 has anxiolytic activity in animal models that
are sensitive to benzodiazepines such as diazepam. However, at
anxiolytic doses in these models, LY354740 produced none of the
unwanted secondary pharmacology associated with diazepam. These data
indicate a functional role for group II mGluRs in fear/anxiety
responses in animals and suggest that compounds in this class may be
beneficial in the treatment of anxiety-related disorders in humans
without the side effects seen with currently prescribed medications.
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