Although relatively few G-protein-coupled receptors are Class C, in recent years, this small family of receptors has become a focal point for the discovery of new and exciting allosteric modulators. The mGlu (metabotropic glutamate) receptors are illustrative in the discovery of both positive and/or negative allosteric modulators with unique pharmacological properties. For instance, allosteric modulators of the mGlu2 receptor act as potentiators of glutamate responses in clonal expression systems and in native tissue assays. These potentiators act to increase the affinity of orthosteric agonists for the mGlu2 receptor and shift potency curves for the agonist to the left. In electrophysiological experiments, the potentiators show a unique activation-state-dependent presynaptic inhibition of glutamate release and significantly enhance the receptor-mediated increase in G-protein binding, as seen with autoradiography. Similarly, potentiators of mGlu5 have been described, as well as allosteric antagonists or inverse agonists of mGlu1 and mGlu5. Binding and activity of the modulators have recently indicated that positive and negative allosteric sites can be, but are not necessarily, overlapping. Compared with orthosteric ligands, these modulators display a unique degree of subtype selectivity within the highly conserved mGlu family of receptors and can have very distinct pharmacological properties, such as neuronal frequency-dependent activity. This short review describes some of the unique features of these mGlu1, mGlu2 and mGlu5 allosteric modulators.

Introduction

Several highly subtype-selective allosteric modulators, which can either inhibit or enhance receptor activation of Class C GPCR (G-protein-coupled receptors), have been described in the literature (see [1] for a recent review of allosteric modulators). The Class C GPCRs share a common structural protein motif, including the separation of the ligand-binding domain (contained within the N-terminus) from the TM (transmembrane) and intracellular domains; the latter is responsible for signal transduction and/or localization to the cellular membrane. Thus, analogous to the orthosteric agonist/antagonists site within the TM regions of Class A GPCRs, an allosteric interaction between a small molecule (or peptide) and the TM region of the receptor could result in either a blockade or enhancement of a ligand-gated activity without directly interacting at the orthosteric site. For instance, this was first shown convincingly within this class of GPCRs at the CaSR (calcium-sensing receptor) [2]. Both naturally occurring and engineered point mutations within the TM region of the CaSR can significantly inhibit or, in fact, enhance the receptor actions [3]. Similarly, small-molecule antagonists and positive modulators of the CaSR have been discovered in recent years and are well characterized.

The Class C GPCRs also include the glutamate and GABA (γ-aminobutyric acid) receptors. The eight cloned mGlu (metabotropic glutamate) receptors are typically subdivided into three groups on the basis of amino acid homology, coupling characteristics and, to some extent, pharmacological preference (see [4] for a review). The group I mGlu receptors, which typically couple with a Gαq-mediated activation of phospholipase C and subsequent intracellular calcium release, include the mGlu1 and mGlu5 receptors. As with the CaSR mentioned above, subtype-selective, non-competitive antagonists have been described for the mGlu1 receptor, e.g. CPCCOEt (7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxylate ethyl ester), and the mGlu5 receptor, e.g. MPEP (2-methyl-6-(phenylethynyl)pyridine) respectively [59]. Using chimaeric receptors and single amino-acid changes in the mGlu1 and mGlu5 receptors, several groups have found that these compounds are truly allosteric negative modulators that interact within the TM regions of their targets, a region distinct from the glutamate site within the N-terminus [7,10,11]. In effect, these compounds are capable of preventing the ‘transduction’ from the glutamate site to the intracellular activation of the G-protein tetramer, presumably by preventing some key change in the orientation or protein tertiary structure of the TM.

An exciting development in GPCR research is the increasing evidence that a positive allosteric interaction of small molecules with a GPCR can also occur, a continuum of activity that can clearly result from orthosteric interactions giving rise to agonist, partial agonist, neutral antagonists or even inverse agonists (which can prevent the constitutive activity found in some GPCRs). Similarly, one might anticipate a range of activities with allosteric modulators, from an allosteric agonist (i.e. one that does not displace an orthosteric agonist, but fully activates the receptor) to an inverse allosteric antagonist. However, there is a unique possibility for allosteric-interacting small molecules to act as potentiators of a receptor. The term potentiator is most commonly used to describe allosteric modulators that, despite possibly increasing the affinity or the maximum amount of receptor bound by an agonist, still require activation via an orthosteric agonist for the receptor-mediated response to occur. Subtype-selective or -preferring potentiators have been described for most of the ligand-gated Class C GPCR family including, as mentioned above, the CaSR and, more recently, the GABAb receptor [12] and mGlu1 [13,14], mGlu2 [15,16], mGlu4 [1719] and mGlu5 receptors [20,21]. These potentiators appear to have many biochemical characteristics in common that are distinct from our classical understanding of orthosteric agonists. Here, we focus on potentiators of the mGlu receptors to illustrate some of these unique pharmacological mechanisms of action.

mGlu2 potentiators: biochemical characteristics of potentiator allosteric modulators

Many of the allosteric modulators have been discovered through the use of functional assays and screening of clonal cell lines expressing the mGlu receptor of interest. Cell lines have usually been engineered by means of chimaeric or promiscuous G-proteins (e.g. Gα15) to allow the monitoring of receptor-dependent increases in intracellular calcium (iCa2+) with calcium-sensitive dyes (fura 2 or Fluo-3) and imaging systems such as the FLIPR (fluorometric imaging plate reader; Molecular Devices). It was by this means that we first discovered a series of 3-pyridylmethyl sulphonamides that were subtype-selective positive allosteric modulators of the mGlu2 receptor [15]. Since that time, it has became clear that these sulphonamide allosteric modulators, such as 4-MPPTS {LY487379; 2,2,2-trifluoro-N-[3-(2-methoxyphenoxy) phenyl]-N-(3-pyridinylmethyl)-ethanesulphonamide}, 3-MPPTS {2,2,2-trifluoro-N-[3-(2-methoxyphenoxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulphonamide} and cyPPTS {2,2,2-trifluoro-N-[3-(cyclopentyloxy)-phenyl]-N-(3-pyridinylmethyl)-ethanesulphonamide}, are typical of GPCR potentiators in many of their biochemical characteristics [15,16]. First and foremost, they are, by definition, allosteric modulators, since they do not bind to the orthosteric site on the receptor. For mGlu2 potentiators, there is no significant displacement of either an antagonist glutamate-site ligand, [3H]-LY341495 (3H-(αS)-α-amino-α-[(1S,2S)-2-carboxycyclopropyl]-9H-xanthene-9-propanoic acid), or an agonist ligand, [3H]-DCG-IV {(2S,2′R,3′R)-2-(2′,3′-dicarboxylcyclopropyl) glycine; [15,15a]}. In addition, 4-MPPTS clearly did not potentiate the agonists activity in chimaeric receptors containing the N-terminal segment of the mGlu2 receptor linked to the TM region of either the mGlu1 or mGlu3 receptors. However, the potentiators do have a response in the reciprocal chimaera consistent with the critical and specific requirement of the TM region of the mGlu2 receptor for potentiator activity (M.P. Johnson and M. Baez, unpublished work). Consequently, these mGlu2-selective ligands appear to interact at an allosteric site within the TM region. Similarly, the Group I antagonists, such as MPEP and CPCCOEt [7,10,11], and the more recently reported GABAb [12] and mGlu1 potentiators [13,14] are all suggested to interact within the TM regions of their receptors.

The molecular mechanism by which a potentiator modulates its GPCR target remains somewhat theoretical. As implied by the name potentiator, these sulphonamide allosteric modulators have a clear dependence on orthosteric agonist-mediated activation in a number of receptor function-based assay formats, such as the aforementioned increased iCa2+ assay [15,15a]. In the iCa2+ assay format, the sulphonamide potentiators will result in leftward shifts in orthosteric agonists including glutamate and 1S,3R-ACPD (1-amino-1S,3R-cyclopen-tanedicarboxylic acid [15,15a]. Theoretically, this leftward shift in potency in a functional assay could result from (i) an increase in G-protein coupling efficiency, (ii) an increase in the number of receptors an orthosteric agonist can activate and/or (iii) an apparent increase in the affinity of the agonist for its orthosteric site. The latter appears to be the case for the sulphonamide mGlu2 potentiators since a 2–3-fold increase in affinity for the orthosteric agonists, glutamate, 1S,3R-ACPD, DCG-IV and LY354740 {(1S,2S,5R,6S-2-aminobicyclo [3.1.0] hexane-2,6-bicaroxylate monohydrate)}, was found in [3H]-DCG-IV agonist binding experiments (see [22] for methods). In contrast, there was no significant alteration in the number of binding sites seen with [3H]-DCG-IV and, moreover, there was no increase in the maximal response seen in functional assays, such as intracellular calcium release [15a]. Thus these results suggest that the potentiators affect agonist affinity without altering the number of receptors or the maximal effect that can occur with mGlu2 activation. However, not all potentiators appear to act by this means. Indeed, we have observed that some potentiators of the mGlu receptors apparently increase the maximal effect without significantly altering orthosteric agonist affinity, whereas other GPCR potentiators appear to affect both agonist affinity and maximal response (M.P. Johnson, unpublished work).

The apparent biochemical characteristics of the potentiators may be dependent also on functional assay methods and end-point measurement. For instance, we have found that the same sulphonamide compounds that induce a change in apparent affinity in a typical intracellular calcium assay will have a very different effect when the more proximal measurement of GTP binding is measured. For instance, the potentiator 3-MPPTS induces slight increases in [35S]GTPγS binding to membranes expressing the human mGlu2 receptor itself, but when combined with an orthosteric agonist, a supramaximal increase in [35S]GTPγS binding was found. The response was clearly dependent on the potentiator concentration, with potencies similar to those seen in other functional assays. Similarly, [35S]GTPγS binding was dependent on orthosteric agonist concentration, as would be anticipated for a potentiator that was dependent on the orthosteric ligand for activation (M.P. Johnson and K. Christensen, unpublished work).

Agonist or modulator-induced GTP binding requires only the first two events to occur, i.e. the dissociation of GDP and association of GTP to the Gα-protein. In contrast, inhibition of cAMP or an increase in calcium requires several additional complex ‘downstream’ actions. Although, classically, an increase in [35S]GTPγS binding has been thought to be synonymous with second-messenger activation, in theory, it might be possible to increase receptor-mediated GTP binding to the G-protein trimer without inducing a subsequent agonist-mediated release of the Gα-protein from the receptor–G-protein complex. Indeed, this hypothesis is more consistent with the present findings where the mGlu2 potentiators induce a receptor-dependent but orthosteric agonist-independent increase in [35S]GTPγS binding, as evidenced by the ability of LY341495 to prevent the potentiator-mediated GTP binding. These sulphonamide potentiators are clearly specific to the mGlu2 receptor since no increase in GTP binding with a similarly constructed mGlu6 line was seen with 3-MPPTS. The potentiators were also able to induce [35S]GTPγS binding in an mGlu2 line containing an inactivating single-point mutation within the glutamate-site domain. Thus the potentiators seem to have a unique interaction, specifically with the mGlu2 receptor. This interaction increases GTP binding, probably by inducing or stabilizing a receptor high-affinity state complex with a GDP-free G-protein heterotrimer. One complicating factor in all these experiments is that receptor activity is measured in an artificially constructed cell-expression system, including G-proteins that may not be relevant to receptor activity in vivo. Therefore it is important to consider that the activity of an allosteric modulator may be dependent on the G-protein-coupling system in a native tissue target of therapeutic interest.

For the mGlu2 receptor sulphonamide potentiators, this was investigated in two ways. First, autoradiographic methods were developed to examine [35S]GTPγS binding on fresh/frozen brain slices from rats and mice. As described above with clonal cell line homogenate preparations, an increase in [35S]GTPγS binding could be seen with either the allosteric modulator 3-MPPTS or the orthosteric agonist LY379268 {(1R,4R,5S,6R)-4-amino-oxabicyclo [3.1.0] hexane-4,6-dicarboxylic acid}. However, the combination of 3-MPPTS and LY379268 significantly enhanced the maximal response seen with even a supramaximal concentration of the orthosteric agonist (see Figure 2). This response corresponded very well with the mGlu2 receptor distribution within certain brain nuclei for rodents, with high degrees of potentiator/agonist-induced [35S]GTPγS binding within such areas as the amygdala, middle layers of the cortex and thalamus. Also, areas largely devoid of mGlu2 binding such as the reticular thalamic and ventral posteromedial thalamic nuclei failed to show potentiator-dependent increases in [35S]GTPγS binding. Thus, not only have we shown that the sulphonamide mGlu2 potentiators are active in a native tissue system, but also that they act in a very similar manner for the receptor-dependent increases in GTP binding.

One of the most exciting and unique characteristics of an allosteric modulator that potentiates a GPCR is that a state-dependent effect may occur, which would not be the case with orthosteric agonists. One illustration of this can again be seen in the sulphonamide potentiators, represented by cyPPTS [16]. When compared with the orthosteric agonist LY354740 in striatal slice preparations stimulating corticostriatal excitatory postsynaptic synaptic potentials, cyPPTS showed a clear dependence on the frequency of presynaptic stimulation. Unlike direct acting agonists, the potentiators still require some level of stimulation by glutamate, resulting in state-dependent responses (see Figure 1). Thus these results imply that the increased levels of the synaptic glutamate released as a result of higher frequency stimulation are required to show a decrease in the EPSPs in striatal slices with potentiators such as cyPPTS, whereas even at a much lower frequency, the orthosteric agonist LY354740 effectively decreased the EPSPs. An orthosteric or allosteric agonist might be expected to induce continuously an inhibitory (e.g. Gi) or stimulatory (e.g. Gq or Gs) action within an axon or dendrite, at least until or unless receptor desensitization occurs. In contrast, the presence of the potentiator alone appeared to result in neither inhibitory nor stimulatory modulation under basal or what is believed to be ‘resting’ levels of synaptic activity. Thus cyPPTS can be said to act simply to sensitize the naturally occurring mGlu2-mediated presynaptic inhibition of glutamate release, altering synaptic transmission only when the levels of glutamate were significantly increased by higher frequency stimulation. In contrast, mGlu2 agonists might be expected to continuously inhibit mGlu2-sensitive glutamatergic pathways and/or result in GPCR desensitization and possible drug tolerance responses in vivo. This might suggest that potentiators would have a unique ability to modulate overexcitation without inducing an inhibition of normal or basal responses that can occur with direct acting presynaptic agonists. Consequently, a potentiator, with its more state-dependent effect, may provide a safer, more easily tolerated and more efficacious means to treat disorders when compared with an agonist for the same therapeutic GPCR target.

Frequency-dependent inhibition of the corticostriatal EPSPs with mGlu2 potentiators

Figure 1
Frequency-dependent inhibition of the corticostriatal EPSPs with mGlu2 potentiators

Corticostriatal projections were stimulated at either low (0.06 Hz) or high (4.0 Hz) frequency, and the inhibition of presynaptic glutamate released was determined by monitoring the excitatory postsynaptic potentials in striatal slices using whole cell patch-clamp methods on rat striatal spiny neurons. Top panel: inhibition of the EPSPs with 1 μM mGlu2/3 orthosteric agonist LY354740 after even low-frequency stimulation. Middle and bottom panels: inhibition of EPSPs with the mGlu2 potentiator cyPPTS after high-frequency stimulation but not after low-frequency stimulation. Probably due to the glutamate-dependent nature of allosteric potentiators, cyPPTS has an effect only when the glutamate levels increase with a more rapid neurotransmitter release.

Figure 1
Frequency-dependent inhibition of the corticostriatal EPSPs with mGlu2 potentiators

Corticostriatal projections were stimulated at either low (0.06 Hz) or high (4.0 Hz) frequency, and the inhibition of presynaptic glutamate released was determined by monitoring the excitatory postsynaptic potentials in striatal slices using whole cell patch-clamp methods on rat striatal spiny neurons. Top panel: inhibition of the EPSPs with 1 μM mGlu2/3 orthosteric agonist LY354740 after even low-frequency stimulation. Middle and bottom panels: inhibition of EPSPs with the mGlu2 potentiator cyPPTS after high-frequency stimulation but not after low-frequency stimulation. Probably due to the glutamate-dependent nature of allosteric potentiators, cyPPTS has an effect only when the glutamate levels increase with a more rapid neurotransmitter release.

Binding of [35S]GTPγS to rat brain slice autoradiography

Figure 2
Binding of [35S]GTPγS to rat brain slice autoradiography

Fresh frozen rat brain slices were treated with the mGlu2/3 agonist LY379268 and/or the mGlu2 potentiator 3-MPPTS, then with [35S]GTPγS at room temperature (24°C) and subsequently exposed to a film for 12 h. Representative slices from triplicate determinations are shown with the relative intensity colorized using Adobe Photoshop 6.0. Comparison of ‘Basal’ with either treatment with 3-MPPTS or LY379268 increased the binding of GTP[S]. However, the combination of the mGlu2/3 agonist and the mGlu2 potentiator significantly enhanced the amount of GTP[S] bound.

Figure 2
Binding of [35S]GTPγS to rat brain slice autoradiography

Fresh frozen rat brain slices were treated with the mGlu2/3 agonist LY379268 and/or the mGlu2 potentiator 3-MPPTS, then with [35S]GTPγS at room temperature (24°C) and subsequently exposed to a film for 12 h. Representative slices from triplicate determinations are shown with the relative intensity colorized using Adobe Photoshop 6.0. Comparison of ‘Basal’ with either treatment with 3-MPPTS or LY379268 increased the binding of GTP[S]. However, the combination of the mGlu2/3 agonist and the mGlu2 potentiator significantly enhanced the amount of GTP[S] bound.

mGlu1 and five allosteric antagonists and potentiators: overlapping or distinct allosteric sites and silent modulators

A number of chemically diverse negative allosteric modulators (i.e. antagonists) have been described for the mGlu1 receptor subtype (see e.g. [23,24]). Here, a distinct advantage is the development of a radioligand and biochemical methods to examine directly the allosteric modulator-binding domain. Within Lilly Research Laboratories, we have characterized several negative allosteric modulators, including [3H]IPTE {2-[4-indan-2-ylamino)-5,6,7,8-tetrahydro-quinazolin-2-ylsulphanyl]-ethanol, HCl}, finding it to be a nanomolar potent and highly subtype-selective antagonist of the mGlu1 receptor [25]. IPTE will block the ability of the orthosteric agonist quisqualate to induce an mGlu1-dependent phosphoinositol hydrolysis or an increase in iCa2+ in clonal cell lines expressing the human or rat mGlu1α splice variant. However, IPTE showed no displacement of agonist binding of [3H]quisqualate to the orthosteric glutamate site contained within the extracellular domain of the mGlu1 receptor, as indicative of an allosteric interaction. As with the other positive and negative allosteric modulators of the mGlu receptor, activity in several chimaeric and point mutation receptor constructs indicates that this is dependent on the TM region of mGlu1. To examine directly the binding domain, we developed a radioligand receptor-binding assay with this antagonist allosteric modulator in homogenates from clonal cell lines expressing the human mGlu1α. As seen in Figure 3, when a number of apparent negative allosteric modulators of the mGlu1 receptor, from diverse chemical structure platforms, were tested in displacement experiments, all were able to displace the [3H]-IPTE with Ki values ranging from 10 nM to 2 μM. However, the orthosteric mGlu1 antagonists, which have been shown to displace [3H]quisqualate, failed to displace the allosteric modulator [3H]IPTE from its binding site on the mGlu1 receptor. Similar findings have been reported by Lavreysen et al. [26] utilizing another radiolabelled allosteric antagonist, [3H]-R214127 (1-(3,4-dihydro-2H-pyrano-[2,3-b]quinolin-7-yl)-2-phenyl-1-ethanone). Thus there are at least partially overlapping binding domains for a number of structurally diverse allosteric antagonists.

Antagonist allosteric modulators of mGlu1 and their affinity for an allosteric site labelled with [3H]IPTE

Figure 3
Antagonist allosteric modulators of mGlu1 and their affinity for an allosteric site labelled with [3H]IPTE

Homogenates from a clonal cell line expressing the human mGlu1a receptor were labelled with the allosteric antagonist [3H]IPTE. Various allosteric antagonists or the orthosteric antagonist LY367385 were utilized to displace the radioligand, and the resulting Ki values are reported here with triplicate determination. BAY36-720, (3aS,6aS)-(hexahydro-5-methylene-6a-(2-naphthalenylmethyl)-1H-cyclopenta[c]furan-1-one); Roche 67-5523, 2-amino-1-ethyl-1,6-dihydro-6-oxo-4-(1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-5-pyrimidinecarbonitrile; LY367385, (αS)-α-amino-4-carboxy-2-methyl-benzeneacetic acid.

Figure 3
Antagonist allosteric modulators of mGlu1 and their affinity for an allosteric site labelled with [3H]IPTE

Homogenates from a clonal cell line expressing the human mGlu1a receptor were labelled with the allosteric antagonist [3H]IPTE. Various allosteric antagonists or the orthosteric antagonist LY367385 were utilized to displace the radioligand, and the resulting Ki values are reported here with triplicate determination. BAY36-720, (3aS,6aS)-(hexahydro-5-methylene-6a-(2-naphthalenylmethyl)-1H-cyclopenta[c]furan-1-one); Roche 67-5523, 2-amino-1-ethyl-1,6-dihydro-6-oxo-4-(1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-5-pyrimidinecarbonitrile; LY367385, (αS)-α-amino-4-carboxy-2-methyl-benzeneacetic acid.

On the basis of the scientific and patent literature, one of the most active areas of research has been the discovery and characterization of allosteric modulators of the mGlu5 receptor subtype. Since the discovery of an mGlu5 subtype-selective allosteric antagonist, MPEP, as reported by Gasparini and co-workers in 1999 [5], numerous advances have been made, including the development of a radiolabelled allosteric ligand, [3H]methoxy-PEPy [3-methoxy-5-(2-pyridinylethynyl)pyridine]. A few potentiators of the mGlu5 receptor have also been described, including DFB (3,3′-diflourobenzaldazine) and, more recently, CPPHA (N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-methyl]phenyl}-2-hydrobenzamide) [20,27]. Interestingly, although both potentiators share similar effects in functional assays, DFB can partially displace the allosteric antagonist radioligand [3H]methoxy-PEPy, whereas CPPHA does not. Thus, whereas structurally diverse allosteric antagonists may share common binding domains, potentiators may or may not share similar binding domains on a GPCR. A common allosteric domain brings to mind the possibility of both allosteric antagonists and potentiators within the same chemical series. A recent report by O'Brien et al. [20] from Merck describes a clear example of positive, negative and even ‘silent’ allosteric modulators from the same benzaldazine chemical platform that yielded DFB. Although DFB is a potentiator at the mGlu5 receptor, substitution of dimethoxy- for the difluoro-group to give DMeOB (3,3′-dimethoxybenzaldazine) yields an allosteric antagonist. Utilizing the radiolabelled [3H]methoxy-PEPy allosteric antagonist, it was further determined that both the potentiator DFB and the antagonist DMeOB partially displaced [3H]methoxy-PEPy with similar potencies. An even more intriguing substitution of dichloro- to give DCB (3,3′-dichlorobenzaldazine) results in a compound that displaces the allosteric radioligand antagonist, but does not result in positive or negative allosteric modulation of the mGlu5 receptor. In other words, DCB can be described as a ‘silent’ or neutral allosteric modulator defined as not altering the response of an orthosteric ligand, but binding to an allosteric site of the GPCR. As one might anticipate, DCB was capable of blocking the allosteric-modulating activity of both the potentiator DFB and the allosteric antagonist DMeOB, thus providing a clear example of silent allosteric modulators that can antagonize selectively allosteric modulators (positive or negative), preventing modulation without effecting orthosteric agonist activation of a GPCR. However, it should be noted that even the ‘silent’ activity of an allosteric modulator for a target GPCR could well be dependent on the functional assay system and/or the G-protein-coupling mechanism within the cell, thus reinforcing the need for confirmation of activity in a native tissue preparation and under several different conditions.

Summary

To summarize, within the family of mGlu receptor allosteric modulators, there is an increasing number of tools available for studies on receptor activation mechanisms and characterization under various conditions. Some aspects of the allosteric modulators may hold true for all, such as the frequency-dependent nature of potentiators or the seemingly sensitive nature of chemical substitution on an allosteric chemical platform. However, other potentiators yield varying biochemical and physiological effects, such as multiple but partially overlapping sites of allosteric domain, or even varying responses with different coupling systems. Thus allosteric modulators will continue to present some added challenges to drug discovery. Nevertheless, it seems most probable that there will be a continuing interest in understanding and, where possible, exploiting for drug discovery allosteric modulation of GPCR including the mGlu receptors.

GPCR Allosterism and Accessory Proteins: New Insights into Drug Discovery: Focused Meeting and Satellite to BioScience2004, held at Organon Laboratories Ltd, Newhouse, Glasgow, U.K., 17 July 2004. Organized and Edited by A. Clark (Organon, U.K.), B. Henry (Organon, U.K.) and J. Presland (Organon, U.K.). Sponsored by Organon Laboratories and Invitrogen.

Abbreviations

     
  • CaSR

    calcium-sensing receptor

  •  
  • DCB

    3,3′-dichlorobenzaldazine

  •  
  • DFB

    3,3′-diflourobenzaldazine

  •  
  • DMeOB

    3,3′-dimethoxybenzaldazine

  •  
  • GABA

    γ-aminobutyric acid

  •  
  • GPCR

    G-protein-coupled receptor

  •  
  • iCa2+

    intracellular calcium

  •  
  • mGlu

    metabotropic glutamate

  •  
  • TM

    transmembrane

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