ReviewAllosteric modulation of metabotropic glutamate receptors: Structural insights and therapeutic potential
Introduction
In addition to eliciting fast excitatory synaptic responses, the neurotransmitter glutamate can modulate neuronal excitability, synaptic transmission, and other cell functions by activation of metabotropic glutamate receptors (mGlus). Due to the ubiquitous distribution of glutamatergic synapses and the broad range of functions of the mGlus, members of this receptor family participate in many different processes in the central nervous system (CNS). As such, mGlus are an attractive target for therapeutic intervention for a range of neurological and psychiatric disorders. mGlus are members of the G protein-coupled receptor (GPCR) superfamily, the largest class of cell-surface receptors. Despite their tractability as drug targets, the majority of GPCR-based drug discovery programs have failed to yield highly selective compounds. The traditional approach to 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 paucity of suitably subtype-selective ligands. This is not surprising given that orthosteric binding sites are often highly conserved between subtypes of a single GPCR subfamily. An alternative approach is to target allosteric sites that are topographically distinct from the orthosteric site, to either enhance or inhibit receptor activation. This approach has been highly successful for ligand-gated ion channels. For example benzodiazepines, positive allosteric modulators (PAMs) of GABAA receptors, are an effective and safe treatment for anxiety and sleep disorders (Mohler et al., 2002). Discovery and characterization of allosteric modulators of GPCRs has gained significant momentum over the last few years, especially since the clinical validity of GPCR allosteric modulators was demonstrated with two allosteric modulators entering the market. In 2004, cinacalcet (an allosteric enhancer of the Calcium-sensing receptor (CaSR)) was approved for the treatment of hyperparathyroidism, a disease associated with CaSR deficiency (Lindberg et al., 2005). In 2007, maraviroc (an allosteric inhibitor of the chemokine receptor CCR5) was approved for the treatment of HIV infections. This drug stabilizes CCR5 receptor conformations that have a lower affinity for the HIV virus, blocking CCR5-dependent entry of HIV-1 into cells (Dorr et al., 2005). Thus, allosteric modulation represents an exciting novel means of targeting GPCRs particularly for CNS disorders, a therapeutic area with one of the highest rates of attrition in drug discovery (Kola and Landis, 2004).
Section snippets
Quantifying allosteric interactions
The binding of an allosteric ligand to its site will change the conformation of the receptor, meaning that the “geography” of the orthosteric site and any other potential receptor-ligand/protein interfaces, also have the potential to change. As a consequence, the binding affinity and/or signaling efficacy of the orthosteric ligand are likely to be modulated, either in a positive or negative manner. The simplest allosteric GPCR model assumes that the binding of an allosteric ligand to its site
Physiological roles of metabotropic glutamate receptors
With the exception of mGlu6 which is localized to the retina, mGlus are ubiquitously expressed throughout the CNS in both neurons and glia, although each subtype is differentially localized in different brain regions (specific brain localizations for each of the mGlu subtypes is reviewed in detail in Ferraguti and Shigemoto, 2006). In recent years, all mGlu subtypes have been genetically deleted in mice; studies using these animals have yielded further insights into the biological functions of
Therapeutic indications for allosteric modulators of metabotropic glutamate receptors
The first allosteric modulator of an mGlu identified was CPCCOEt, a NAM of mGlu1 (Annoura et al., 1996). Selective promising allosteric modulators have been identified for many mGlu subtypes (see Fig. 2 and Table 1) and are exciting potential therapeutics for a variety of CNS-related disorders including Alzheimer’s disease (Lee et al., 2004), anxiety disorders (Spooren and Gasparini, 2004, Swanson et al., 2005), depression (Palucha and Pilc, 2007), epilepsy (Alexander and Godwin, 2006, Ure
Common allosteric sites within and between metabotropic glutamate receptors
One of the continuing challenges faced in drug discovery is establishing suitably subtype selective ligands. Although allosteric ligands have better specificity than orthosteric ligands, there are numerous examples of allosteric modulators that interact with multiple receptor subtypes. As mentioned above, MPEP, an mGlu5 NAM, is an mGlu4 PAM (Mathiesen et al., 2003), while DFB and CPPHA (mGlu5 PAMs) are also weak mGlu4 NAMs (O’Brien et al., 2003, O’Brien et al., 2004). Similarly, PHCCC, an mGlu4
Conclusions
Since the discovery of the first mGlu allosteric modulator in 1996, the field of mGlu allosteric modulation has seen a number of major advances. For the majority of subtypes, selective allosteric modulators have now been discovered. Positive, negative and neutral allosteric ligands have been identified for some subtypes, providing much needed pharmacological tools to probe the physiological roles of these important receptors. With the clinical validity of allosteric modulation of GPCRs as a
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