LY354740: A systemically active mGlu2/mGlu3 receptor agonist

In summary, in vitro and in vivo studies have shown LY354740 to be a highly novel pharmacological agent with multiple possible therapeutic applications: 1. LY354740 is a nM potent agonist for group II mGlu receptors and has no appreciable activities at ionotropic glutamate receptors or other subtypes of mGlu receptors at concentrations which activate group II mGlu2 and mGlu3 receptors. 2. Modulation of synaptic transmission by LY354740 appears to involve presynaptic and possibly postsynaptic mechanisms. LY354740 acts at select synapses where mGlu2/mGlu3 receptors are expressed to suppress excitatory transmission when evoked by various means that include excitatory 5HT(2A) receptors and depolarization-induced release of glutamate. 3. LY354740 has shown activity in certain benzodiazepine-sensitive models of fear/anxiety in animals without the secondary pharmacology (i.e., sedation, motor impairment) observed with other anxiolytics. 4. LY354740 has been reported to suppress withdrawal phenomena associated with diazepam, nicotine, and morphine in rats. 5. LY354740 has been reported to selectively suppress release of glutamate and behavioral disruptions subsequent to PCP administration in rats. 6. LY354740 has been shown to protect excitotoxic injury to neurons in vitro and provide some protection against traumatic and ischemic injury to neurons. Additional studies, however, are warranted to clarify the neuroprotectant properties of this mechanism for acute stroke. The above-described disorders of the CNS have in common excessive or pathologically enhanced glutamate transmission in specific synapses and neuronal circuits of the brain. Thus, activation of mGlu2/mGlu3 receptors by LY354740 represents a highly novel mechanism for suppression of pathologically enhanced glutamate transmission, and the possible treatment of certain psychiatric and neurological conditions (Fig. 3).