Allosteric Modulation of Metabotropic Glutamate Receptors

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Abstract

The development of receptor subtype-selective ligands by targeting allosteric sites of G protein-coupled receptors (GPCRs) has proven highly successful in recent years. One GPCR family that has greatly benefited from this approach is the metabotropic glutamate receptors (mGlus). These family C GPCRs participate in the neuromodulatory actions of glutamate throughout the CNS, where they play a number of key roles in regulating synaptic transmission and neuronal excitability. A large number of mGlu subtype-selective allosteric modulators have been identified, the majority of which are thought to bind within the transmembrane regions of the receptor. These modulators can either enhance or inhibit mGlu functional responses and, together with mGlu knockout mice, have furthered the establishment of the physiologic roles of many mGlu subtypes. Numerous pharmacological and receptor mutagenesis studies have been aimed at providing a greater mechanistic understanding of the interaction of mGlu allosteric modulators with the receptor, which have revealed evidence for common allosteric binding sites across multiple mGlu subtypes and the presence for multiple allosteric sites within a single mGlu subtype. Recent data have also revealed that mGlu allosteric modulators can display functional selectivity toward particular signal transduction cascades downstream of an individual mGlu subtype. Studies continue to validate the therapeutic utility of mGlu allosteric modulators as a potential therapeutic approach for a number of disorders including anxiety, schizophrenia, Parkinson's disease, and Fragile X syndrome.

Introduction

Despite their tractability as drug targets, the majority of G protein-coupled receptor (GPCR)-based drug discovery programs have failed to yield highly selective compounds. Further, CNS disorders represent a therapeutic area with one of the highest rates of attrition in drug discovery (Kola & Landis, 2004). The traditional approach to targeting GPCRs in drug discovery has been to target the endogenous ligand (orthosteric)-binding site, to either mimic or block the actions of the endogenous neurotransmitter or hormone in a competitive manner. However, this approach has suffered from a lack of suitably subtype-selective ligands, both as tools to probe physiology and pathophysiology experimentally, and as therapeutic candidates. An alternative approach is to target allosteric sites that are topographically distinct from the orthosteric site, to either enhance (positive allosteric modulators, PAMs) or inhibit (negative allosteric modulators, NAMs) receptor activation. These allosteric modulators, offer a number of potential advantages over their orthosteric counterparts. In many cases, allosteric sites consist of regions on the receptor that show greater sequence divergence than orthosteric sites and as such have greater potential for subtype-selective ligand development. Further, in the case of an allosteric modulator that has no intrinsic activity, there is the capacity to “fine-tune” the response to the endogenous ligand, thereby retaining the spatial and temporal aspects of neurotransmission. Alternatively, allosteric modulators can also have intrinsic efficacy, activating the receptor alone (allosteric agonists) or neutral efficacy, having no effects on the receptor alone but competing with the activity of other allosteric modulators. Because the pharmacological effects of allosteric ligands are limited by their cooperativity, there is a ceiling level to their effect, which may provide greater margin of safety in the case of overdose. One disadvantage of allosteric modulators is that unlike orthosteric ligands, pure allosteric modulators with no intrinsic efficacy rely on the presence of endogenous ligand for efficacy.

Targeting allosteric sites to either enhance or inhibit receptor activation has proven to be highly successful for ligand-gated ion channels. For example, the mechanism of action of benzodiazepines is allosteric enhancement of GABAA receptor activity, which provides a safe and effective treatment for anxiety and sleep disorders (Mohler et al., 2002). Two GPCR allosteric modulators have now entered the market, demonstrating the clinical validity of this approach. The first of these modulators, Cinacalcet, is a PAM of the calcium-sensing receptor (CaSR) and was approved in 2004 for the treatment of hyperparathyroidism, a disease associated with CaSR deficiency (Lindberg et al., 2005). The second, Maraviroc, stabilizes C–C chemokine receptor type 5 (CCR5) receptor conformations that have a lower affinity for the HIV virus, allosterically inhibiting CCR5-dependent entry of HIV-1 into cells (Dorr et al., 2005) and was approved for the treatment of HIV infections in 2007. Consequently, discovery and characterization of GPCR allosteric modulators have gained significant momentum in the past two decades and represent exciting novel means of targeting therapeutically relevant GPCRs. Arguably, one of the most well-studied GPCR families with respect to allosteric modulation are the metabotropic glutamate receptors (mGlus). Indeed, the full spectrum of allosteric ligands has been discovered for these receptors.

Section snippets

Metabotropic Glutamate Receptors

The neuromodulatory actions of the major neurotransmitter glutamate within the CNS are mediated by activation of the mGlus. There are eight mGlu subtypes, and with the exception of mGlu6, which is primarily expressed in the retina, mGlus are expressed throughout the CNS. The individual subtypes show varied distribution in different brain areas, can be found both pre and postsynaptically (Fig. 1), participate in many different CNS processes, and are attractive therapeutic targets for a number of

Group I mGlus

The first mGlu allosteric modulator was identified when the selective mGlu1 antagonist CPCCOEt (Annoura et al., 1996) was determined to act via a noncompetitive mechanism (Litschig et al., 1999), which marked a major advance in supporting the rationale of targeting allosteric sites for discovery of highly subtype-selective mGlu antagonists. Several structurally distinct mGlu1 NAMs with nanomolar potencies have been published since, including Bay 36-7620 (Carroll et al., 2001), JNJ16259685 (

Quantifying Allosteric Interactions

The binding of an allosteric modulator has the potential to modulate, either in a positive or negative manner, the binding affinity and/or signaling efficacy of an orthosteric ligand. This is a consequence of changes in the conformation of the receptor when it is simultaneously bound by more than one ligand, resulting in altered “geography” of the orthosteric site and also receptor/protein interfaces. The simplest model of GPCR allosteric interactions, referred to as the allosteric ternary

Structural Determinants of mGlu Allosteric Modulator Binding

Through the use of chimeric and truncated receptor constructs, all currently identified allosteric modulators of mGlus are known to bind within the transmembrane-spanning regions of the receptor (Brauner-Osborne et al., 1999, Carroll et al., 2001, Gasparini et al., 2001, Goudet et al., 2004, Knoflach et al., 2001, Litschig et al., 1999, Maj et al., 2003, Mitsukawa et al., 2005, Pagano et al., 2000). Interestingly, truncation of the N-terminal extracellular VFD, but retention of an intact

Functional Selectivity of mGlu Allosteric Modulation

Within the GPCR field, it is becoming increasingly evident that the consequences of receptor activation are not limited to G protein-coupling alone, with the overall cellular response to GPCR activation arising from a myriad of receptor–effector interactions. Indeed, it is now well established that ligand pharmacology is dependent upon the measure of receptor activation employed, a phenomenon referred to by many names including “stimulus trafficking,” “biased agonism,” and “functional

mGlu1 NAMs for Pain

Multiple studies have demonstrated the efficacy of mGlu1 NAMs in models of analgesia. For example, the mGlu1 NAM YM-298198 is analgesic in the streptozotocin-induced hyperalgesia mouse model (Kohara et al., 2005), and FTIDC displays analgesic effects in the formalin test (Satow et al., 2008). In addition, the mGlu1 NAM CPCCOEt dose-dependently reversed capsaicin-induced sensitization in spinothalamic tract cells in vivo demonstrating the potential utility of mGlu1-selective NAMs for the

Conclusion

Within the past 15 years, selective allosteric modulators have been developed for the vast majority of the mGlus. This advance, together with the development of mGlu KO mice, has greatly led to our better understanding of the roles of individual mGlu subtypes in a number of systems. Within this time, the mGlu allosteric modulators field has also made significant advances in the understanding of how and where these compounds interact with the receptor. These studies have suggested commonalities

Acknowledgments

The authors would like to acknowledge funding from the National Institute of Mental Health (D. J. S., P. J. C), an American Australian Association Merck Co. Foundation fellowship (K. J. G.), and a National Institute of Mental Health Kirschstein National Research Service Award (J. M. R.).

Conflicts of Interest: Dr. Conn has served as a consultant over the past 3 years for: Merck and Co., Johnson and Johnson, Hoffman La Roche, GlaxoSmithKline, Lundbeck Research USA, Epix Pharmaceuticals,

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