Anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors

ABSTRACT 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 (ED 50 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. Glutamate is the major excitatory neurotransmitter in the mammalian CNS, contributing excitatory input to virtually all neurons of the brain and spinal cord. The ubiquitous nature of glutamate excitation supports a role for glutamatergic neurotransmission in most physiological processes of the CNS including sensory and motor functions, central regulation of respiratory and cardiovascular centers, cognition and regulation of perception and emotion. Similarly, altered glutamatergic neuronal transmission has also been hypothesized to have a central role in many neurological and psychiatric disorders, including neurodegenerative diseases, epilepsy, schizophrenia and anxiety Until recently, the effects of glutamate were thought to be exclusively mediated by ion channel-mediated ionotropic receptors (iGluRs), which include NMDA, AMPA and kainate receptor subtypes Group I mGluRs include mGluR 1 and mGluR 5 , group II receptors include mGluR 2 and mGluR 3 and group III mGluRs consist of mGluR 4 , mGluR 6 , mGluR 7 and mGluR 8 . When expressed in nonneuronal cells, group I mGluRs couple to the activation of phosphoinositide hydrolysis, although group II and group III mGluRs are negatively linked to cAMP formation. Each mGluR subtype is uniquely and differentially distributed in the CNS. Group II mGluRs (mGluR 2 and mGluR 3 ) are highly localized within forebrain regions in the rat suggesting specific roles in modulation of glutamatergic transmission in those region