Metabotropic glutamate 2/3 receptors as drug targets Gerard J Marek Metabotropic glutamate receptors are a family of class III G- protein-coupled receptors comprising eight members (mGluR1– 8), which are an attractive target in the central nervous system because of the widespread use of glutamate as the principal excitatory amino acid transmitter. The unique pharmacology of class III G-protein coupled receptors, their forebrain localization in key limbic-related cortical/thalamic/striatal/amygdaloid circuits, and the promise of subtle modulation of glutamatergic neurotransmission make these receptors intriguing targets for a wide variety of neuropsychiatric disorders. Addresses Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285, USA e-mail: marekgj@lilly.com Current Opinion in Pharmacology 2004, 4:18–22 This review comes from a themed issue on Neurosciences Edited by Joseph Coyle 1471-4892/$ – see front matter ß 2003 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2003.10.003 Abbreviations GAD generalized anxiety disorder GPCR G-protein-coupled receptor mGluR metabotropic glutamate receptor NMDA N-methyl-D-aspartate PCP phencyclidine Introduction Metabotropic glutamate receptors (mGluRs) are a major family of class III G-protein-coupled receptors (GCPRs), which also include g-aminobutyric acid-B receptors and several chemoreceptors. A unique feature of class III GPCRs is a large extracellular domain containing the glutamate binding site [1]. Thus, mGluRs have signif- icantly different cDNA and protein sequences from the bulk of monoaminergic and peptide GPCRs that have been the traditional targets of the pharmaceutical indus- try. As a consequence, mGluR ligands might exemplify Ehrlich’s pharmacological ‘silver bullet’ more than any previous drug chemotype. Pharmacologically, most is known about the group II members (mGluR2/3) of the mGluR family, which are known to be negatively coupled to adenylyl cyclase as a principle transduction pathway. Converging results from in situ mRNA hybridization and specific antibodies have suggested that mGluR2 and mGluR3 are localized widely throughout both separate and overlapping circuits of relevance for neuropsychiatric and neurological disorders, such as the neocortex, thalamus, striatum, amygdala and hippocampus [2–4]. A third critical feature of mGluRs is that they do not mediate fast excitatory transmission. Rather, they appear to have a modulatory effect on glutamatergic transmission. Although mGluR2/3 have both postsynaptic and presy- naptic localization, it is the latter site of action that makes these receptors an attractive pharmacological target [5]. Most of the widely used neuropsychiatric drugs have actions at either a neurotransmitter transporter or a pre- synaptic autoreceptor. Thus, mGluR2/3 appear uniquely positioned to play a major role in the treatment of neu- ropsychiatric and neurological disorders for all three rea- sons cited above (Box 1). Anxiety disorders The most impressive collection of preclinical and clinical studies involving mGluR2/3 agonists suggests that this class of compounds may have efficacy in generalized anxiety disorder (GAD) or panic disorder [6]. LY354740, a structural analog of glutamate and a highly selective mGluR2/3 agonist, was found to block the expression of fear-potentiated startle in rats at doses that do not pro- duce sedation [7]. Infusion of LY354740 directly into the amygdala blocked both the performance of fear-poten- tiated startle and fear learning, and the mGluR2/3 antago- nist LY341495 blocked the suppressant action of mGluR2/3 agonists [8]. Furthermore, the effects of sys- temic administration of LY354740 differs from those of the benzodiazepine diazepam in that the mGluR2/3 agonist does not block fear conditioning while reducing fear-potentiated startle, and a double dissociation exists for blocking the suppressant action of the mGluR2/3 agonist and diazepam by the mGluR2/3 antagonist LY341495 and the g-aminobutyric acid-A inverse agonist flumazenil [9]. Translation of these effects to humans was demonstrated recently by a report showing that LY354740 blocked the fear-potentiated startle reflex to shock anticipation but not to darkness. Furthermore, healthy subjects also reported subjective decreased state anxiety and negative affectivity in the absence of sedation [10  ]. In addition to previous reports of an anxiolytic action of LY354740 in traditional anxiety models such as the Vogel conflict drinking test [11] and the elevated plus-maze model [12] in rats, LY354740 blocked lactate- induced panic-like responses (changes in autonomic func- tion and the social interaction test) in panic-prone rats [13]. Because the latter result predicts efficacy in treating panic attacks, LY354740 was tested in patients with panic Current Opinion in Pharmacology 2004, 4:18–22 www.sciencedirect.com