Group II mGlu agonists

mGlu2 and mGlu3 are expressed in brain areas important for anxiety disorders, e.g., amygdala, hippocampus, and prefrontal cortex. mGlu2 receptors are located on glutamate-releasing nerve terminals where they suppress glutamate release, whereas mGlu3 is found both pre- and postsynaptically, and on glia. Activation of group II mGlus also suppresses the release of GABA, monoamines, and neuropeptides.125 The constrained glutamate analogs LY354740 and MGS 0028 (Figure 11a) are potent, selective agonists of mGlu2 and mGlu3 receptors.124'126 Systemic administration of LY354740 produces anxiolytic effects in a range of animal models, including fear potentiated startle, EPM, and conflict tests. Where compared, the anxiolytic effects of these compounds are similar to those for standard BZs, but occur in the absence of sedation or ataxia. LY354740 may, however, disrupt memory processes in animals,127 although the compound reduced ketamine-induced deficits in working memory in humans.128 LY354740 demonstrated efficacy in two clinical studies: carbon dioxide-induced anxiety in panic attack patients and a phase II trial in GAD patients.124 LY544344, a prodrug of LY354740, is in phase III trials for anxiety. It is unclear whether agonist activity at both mGlu2 and mGlu3 is required for the efficacy of LY354740, since anxiolytic efficacy is lost in both mGlu2 or mGlu3 knockout mice.129 However, compounds with mGlu2 selectivity have also shown anxiolytic activity in animal models (see below).

Allosteric modulators of mGlus have been described that bind to sites on the receptor distinct from the orthotopic glutamate recognition site, and act as positive, negative, or neutral allosteric modulators of glutamate-induced receptor function. Several classes of positive allosteric modulators with high affinity and selectivity for mGlu2 have been reported (Figure 11b). These have better 'drug-like' properties than glutamate site agonists and show greater selectivity towards mGlu subtypes. In addition, they have the theoretical advantage over glutamate site agonists in that their action is to potentiate mGlu receptor function when it is activated physiologically by the endogenous ligand, rather than indiscriminate activation by an exogenous agonist. Positive allosteric modulators of mGlu2 are anxiolytic in animal models.130

Figure 11 Anxiolytic mGlu receptor ligands: (a) mGlu2/3 agonists; (b) mGlu2-positive allosteric modulators; and (c) mGlu1/5 antagonists.
Getting to Know Anxiety

Getting to Know Anxiety

Stop Letting Anxiety Rule Your Life And Take Back The Control You Desire Right Now! You don't have to keep letting your anxiety disorder run your life. You can take back your inner power and change your life for the better starting today! In order to have control of a thing, you first must understand it. And that is what this handy little guide will help you do. Understand this illness for what it is. And, what it isn't.

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