LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress

Metabotropic glutamate (mGlu) receptors, which include mGlu1-8 receptors, are a heterogeneous family of G-protein coupled receptors (GPCRs) that function to modulate neuronal excitation and plasticity via pre-synaptic, post-synaptic and glial mechanisms. Agonists for group II mGlu receptors (mGlu2 and mGlu3), such as LY354740, have been shown to suppress enhanced glutamatergic excitations in brain synapses known to be involved in the expression of fear/anxiety in animals and humans. Systemic administration of LY354740 increases open-arm time in the elevated plus maze in mice under conditions of moderate to severe stress, blocks the expression but not development of fear-potentiated startle in rats, prevents lactate-induced panic-like responses in panic-prone rats, and attenuates certain physiological, behavioral, and neurochemical consequences of acute stress in rodents. In these preclinical models, LY354740 does not produce the side-effects (e.g. sedation) that are associated with other anxiolytic agents such as benzodiazepines. Early clinical results with LY354740 have demonstrated safety and efficacy in a human anxiety model (panic provocation induced by CO2 challenge). Collectively, these data indicate mGlu2/3 receptor agonists such as LY354740 represent a promising new approach for treatment of anxiety and stress-related disorders in humans.