Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation

Karen J Gregory; P Jeffrey Conn

doi:10.1124/mol.114.097220

. 2015 Jul;88(1):188–202. doi: 10.1124/mol.114.097220

Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation

Karen J Gregory ¹, P Jeffrey Conn ^1,^✉

PMCID: PMC4468636 PMID: 25808929

Abstract

The metabotropic glutamate (mGlu) receptors are a group of eight family C G protein–coupled receptors that are expressed throughout the central nervous system (CNS) and periphery. Within the CNS the different subtypes are found in neurons, both pre- and/or postsynaptically, where they mediate modulatory roles and in glial cells. The mGlu receptor family provides attractive targets for numerous psychiatric and neurologic disorders, with the majority of discovery programs focused on targeting allosteric sites, with allosteric ligands now available for all mGlu receptor subtypes. However, the development of allosteric ligands remains challenging. Biased modulation, probe dependence, and molecular switches all contribute to the complex molecular pharmacology exhibited by mGlu receptor allosteric ligands. In recent years we have made significant progress in our understanding of this molecular complexity coupled with an increased understanding of the structural basis of mGlu allosteric modulation.

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Introduction

Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS), eliciting its effects via two distinct receptor classes. The ionotropic glutamate receptors are ligand-gated ion channels that mediate fast synaptic responses. The metabotropic glutamate (mGlu) receptors are G protein–coupled receptors (GPCRs) that play a modulatory role in the CNS. Ubiquitously expressed throughout the CNS in glia and neurons, found both pre- and postsynaptically, the mGlu receptors are involved in a broad range of physiologic functions in the brain. Comprised of eight members, the mGlu receptor family is often subclassified into three groups based on homology, pharmacology, and G protein coupling. Group I includes mGlu₁ and mGlu₅ that preferentially couple to G_q/11 and are typically found postsynaptically. Group II, mGlu₂ and mGlu₃; and group III, mGlu₄, mGlu₆, mGlu₇, and mGlu₈, members couple to G_i/o and with the exception of mGlu₆, which is exclusively found in the retina, are predominantly located presynaptically. Multiple recent reviews have extensively discussed the roles of mGlu receptors in different neuronal circuits, modulating synaptic transmission, neuronal excitability, and other cellular functions within the CNS (Conn and Pin, 1997; Anwyl, 1999; Valenti et al., 2002; Coutinho and Knopfel, 2002; Bellone et al., 2008; Pinheiro and Mulle, 2008) as well as physiology in the periphery (Julio-Pieper et al., 2011). Based on this understanding, targeting activation or inhibition of specific mGlu receptor subtypes may provide a therapeutic benefit for a range of psychiatric and neurologic disorders. For neuropathic pain, inhibition of mGlu₁ is being pursued as a therapeutic intervention with success reported in preclinical models (Mabire et al., 2005; Bennett et al., 2012). Agonists of group II receptors have reached clinical trials for schizophrenia and anxiety with varying success (Schoepp et al., 2003; Patil et al., 2007; Dunayevich et al., 2008; Kinon et al., 2011). Group II mGlu receptors are also attractive targets for addiction and depression (Ma et al., 2007; Moussawi and Kalivas, 2010; Chaki et al., 2013). Inhibitors of mGlu₅ have demonstrated efficacy in preclinical studies for anxiety, depression, and Parkinson’s disease Levodopa-induced dyskinesias (Porter et al., 2005; Li et al., 2006; Belozertseva et al., 2007; Rylander et al., 2010; Hughes et al., 2013). Promisingly, multiple mGlu₅ inhibitors have reached (Berry-Kravis et al., 2009; Keywood et al., 2009; Zerbib et al., 2010) or are currently in phase II clinical trials (www.clinicalTrials.gov) with varying successes and failures for fragile X syndrome, Parkinson’s disease Levodopa-induced dyskinesias, gastroesophogeal reflux disorder, and migraine. On the other hand, activators and/or potentiators of mGlu₅ have efficacy in preclinical models for schizophrenia and cognition (Moghaddam, 2004; Noetzel et al., 2012a). Activation or potentiation of group III mGlu receptors, in particular mGlu₄, has therapeutic potential for Parkinson’s disease (Marino et al., 2003; Jones et al., 2012), with mGlu₄ also a potential target for pain (Vilar et al., 2013) and autism (Becker et al., 2014).

Therapeutic Targeting of mGlus with Allosteric Modulators

The prevailing strategy for GPCR-based drug discovery has been to target the endogenous ligand binding site, referred to as an orthosteric site, to competitively block or mimic the actions of the endogenous ligand. However, multiple receptor families and transporters recognize glutamate, and as such, glutamate binding pockets are highly conserved such that orthosteric ligands often lack sufficient selectivity. Based on this and difficulties in optimizing glutamate analogs as drug candidates, mGlu receptor-based drug discovery programs have turned their attention to alternative strategies to develop more selective agents. One such approach is to target allosteric binding sites that are topographically distinct from the orthosteric site, such that the receptor can be simultaneously bound by more than one ligand. These ligands are referred to as allosteric modulators and have the capacity to perturb the affinity and/or efficacy of an orthosteric ligand. Because allosteric sites are often located in regions of the receptor that show greater diversity between subtypes, allosteric modulators offer the potential for greater subtype selectivity than their orthosteric counterparts. Allosteric modulators may potentiate or inhibit the affinity and/or efficacy of an orthosteric ligand, a property referred to as “cooperativity.” A potentiator that has positive cooperativity with the orthosteric ligand is a positive allosteric modulator (PAM), whereas an inhibitor is a negative allosteric modulator (NAM). Cooperativity is saturable, therefore allosteric modulators have the theoretical advantage of being safer in the case of overdose, as there is a limit to the modulatory effect. A third class of ligands that interact with allosteric sites but have neutral cooperativity with the orthosteric ligand are called neutral allosteric ligands and represent excellent pharmacological tools for dissecting allosteric modulator pharmacology (Christopoulos et al., 2014). A third advantage of allosteric modulators is the potential to maintain spatial and temporal aspects of receptor activation, i.e., modulation will only occur when and where the orthosteric agonist is present. However, it is important to note that allosteric ligands may possess intrinsic efficacy (either positive or inverse) in addition to, or exclusive of, cooperativity with orthosteric ligands (Annoura et al., 1996; Litschig et al., 1999; Niswender et al., 2008; Duvoisin et al., 2010; Gregory et al., 2012, 2013a; Noetzel et al., 2012b; Lavreysen et al., 2013; Rook et al., 2013). The first allosteric modulator discovered for the mGlu family was CPCCOEt [7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester], an mGlu₁ NAM of multiple orthosteric agonists, including glutamate (Annoura et al., 1996; Litschig et al., 1999). The past 15 years has seen the discovery of selective allosteric modulators for most of the mGlu family, and for many subtypes multiple chemotypes and different classes of allosteric ligands have been disclosed (Tables 1, 2, and 3).

TABLE 1.

Molecular pharmacology of selected examples of allosteric ligands for group I metabotropic glutamate receptors

Ligand/Selectivity		Allosteric Pharmacology	References
CPCCOEt	1	NAM: glutamate, DHPG, quisqualate, and ACPD mediated inositol phosphate accumulation (IP₁); glutamate mediated intracellular Ca²⁺ mobilization (iCa²⁺); quisqualate induced changes in cell impedance (xCelligence); extracellular Ca²⁺ induced changes in iCa²⁺. NAL: [³H]glutamate binding.	Annoura et al., 1996; Litschig et al., 1999; Scandroglio et al., 2010; Jiang et al., 2014
JNJ-16259685	1 > >5	NAM: glutamate mediated iCa²⁺ and IP₁; quisqualate induced changes in cell impedance (xCelligence). Inverse agonist: IP₁. NAL: [³H]quisqualate binding.	Lavreysen et al., 2004; Scandroglio et al., 2010;
R214127	1/5	NAM: glutamate mediated iCa²⁺. Inverse agonist: IP₁.	Lavreysen et al., 2003
Ro 67-7476	1	PAM: glutamate efficacy for mediating iCa²⁺ and cAMP accumulation. Agonist: pERK1/2.	Hemstapat et al., 2006; Sheffler et al., 2008
Ro0711401	1	Agonist: iCa²⁺. PAM: glutamate mediated K⁺ currents via GIRK activation.	Vieira et al., 2009
YM-298198	1	NAM: glutamate induced IP₁; quisqualate induced changes in cell impedance (xCelligence). NAL: orthosteric agonists and affinity of radiolabeled ligand.	Kohara et al., 2005; Scandroglio et al., 2010
5MPEP	5	NAL: glutamate efficacy for iCa²⁺; glutamate and DHPG efficacy for IP₁; quisqualate affinity.	Rodriguez et al., 2005; Chen et al., 2007, 2008; Ayala et al., 2009; Hammond et al., 2010; Bradley et al., 2011
5PAM523	5	PAM: glutamate efficacy for iCa^2+. NAL: [³H]quisqualate binding.	Parmentier-Batteur et al., 2014
ADX47273	5	PAM: quisqualate affinity; quisqualate efficacy for IP₁.	Bradley et al., 2011
CDPPB	5	PAM: glutamate efficacy for iCa²⁺; quisqualate affinity; quisqualate efficacy for IP_1. PAM-agonist: glutamate efficacy for iCa²⁺, pERK1/2 and p-Akt.	Chen et al., 2007; Bradley et al., 2011; Gregory et al., 2012; Doria et al., 2013; Parmentier-Batteur et al., 2014
CPPHA	5 > 1 > 4/8	mGlu₅ PAM: glutamate efficacy for iCa²⁺; quisqualate efficacy for IP₁ and iCa²⁺_. mGlu₅ NAL: quisqualate and glutamate affinity. mGlu₅ PAM-agonist: glutamate efficacy for pERK1/2. NAM-agonist: DHPG efficacy for pERK1/2 (cortical astrocytes). mGlu₄ and mGlu₈ NAM: glutamate-mediated Ca²⁺ signaling.	O’Brien et al., 2004; Zhang et al., 2005; Chen et al., 2008; Bradley et al., 2011; Gregory et al., 2012;
DPFE	5	PAM-agonist: glutamate efficacy for iCa²⁺and pERK1/2.	Gregory et al., 2013b
M-5MPEP	5	NAM (low cooperativity): glutamate efficacy for iCa²⁺; quisqualate and DHPG efficacy for IP₁. NAM: glutamate, DHPG and quisqualate mediated Ca²⁺ oscillations; glutamate efficacy for pERK1/2. NAL: quisqualate affinity.	Rodriguez et al., 2005; Bradley et al., 2011; Gregory et al., 2012
MPEP	5 > >4	mGlu₅ NAM: glutamate efficacy for iCa²⁺and pERK1/2; quisqualate and DHPG stimulated IP₁; glutamate, DHPG and quisqualate induced Ca²⁺ oscillations. mGlu₅ inverse agonist: IP₁. mGlu₅ NAL: quisqualate and glutamate affinity. mGlu₄ PAM-agonist: L-AP4 mediated iCa²⁺. mGlu₄ PAM: L-AP4 induced changes in VFT.	Gasparini et al., 1999; Chen et al., 2007; Bradley et al., 2011; Gregory et al., 2012; Rovira et al., 2015
VU0357121	5	NAL: glutamate affinity. PAM: glutamate efficacy for iCa²⁺. PAM-agonist: glutamate efficacy for pERK1/2.	Hammond et al., 2010; Gregory et al., 2012
VU0360172	5	PAM: glutamate efficacy for iCa²⁺. NAL: glutamate affinity. PAM-agonist: glutamate efficacy for pERK1/2.	Gregory et al., 2012

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ACPD, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid; ADX47273, (4-fluorophenyl)-[(3S)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone; DPFE, 1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((4-fluorobenzyl)oxy)ethanone; GIRK, G protein–coupled inwardly rectifying potassium channel; JNJ-16259685, 3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl-(4-methoxycyclohexyl)methanone; NAL, neutral allosteric ligand; 5PAM523, 5-fluoro-2-{3-[(3S,6R)-1-[(4-fluorophenyl)carbonyl]-6-methylpiperidin-3-yl]-1,2,4-oxadiazol-5-yl}pyridine; Ro0711401, N-[4-(trifluoromethyl)-1,3-oxazol-2-yl]-9H-xanthene-9-carboxamide; Ro 67-7476, (S)-2-(4-fluorophenyl)-1-(toluene-4-sulfonyl)pyrrolidine; VU0360172, N-cyclobutyl-6-[2-(3-fluorophenyl)ethynyl]pyridine-3-carboxamide; YM-298198, 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide.

TABLE 2.

Molecular pharmacology of selected allosteric ligands for group II metabotropic glutamate receptors

Ligand/Selectivity		Allosteric Pharmacology	References
BINA	2	PAM-agonist: glutamate stimulated [³⁵S]GTPγS binding at human mGlu₂. PAM: glutamate stimulated [³⁵S]GTPγS binding at rat mGlu₂ and iCa²⁺ at human and rat mGlu₂; [³H]DCG-IV binding to human mGlu₂; LY541850 mediated decreases in Ca²⁺ oscillation frequency in primary neuronal cultures. NAL: [³H]LY341495 binding to human mGlu₂, LY379268 mediated decreases in Ca²⁺ oscillation frequency in primary neuronal cultures.	Galici et al., 2006; Hemstapat et al., 2007; Lavreysen et al., 2013; Sanger et al., 2013
CBiPES		PAM: glutamate mediated iCa²⁺; LY379268 and LY541850 mediated decreases in Ca²⁺ oscillation frequency in primary neuronal cultures.	Johnson et al., 2005; Sanger et al., 2013
JNJ-40068782	2	PAM-agonist: glutamate stimulated [³⁵S]GTPγS binding and iCa²⁺ at human mGlu₂. PAM: glutamate stimulated [³⁵S]GTPγS binding at rat mGlu₂; [³H]DCG-IV binding to human mGlu₂; glutamate affinity (displacement of [³H]DCG-IV). NAL: [³H]LY341495 binding.	Lavreysen et al., 2013
LY2607540 (THIIC)	2	PAM-agonist: glutamate stimulation of iCa²⁺ and [³⁵S]GTPγS binding at human receptor. PAM: glutamate stimulation of iCa²⁺ and [³⁵S]GTPγS binding at rat receptor.	Fell et al., 2011; Lavreysen et al., 2013
LY487379	2	PAM-agonist: glutamate stimulation of [³⁵S]GTPγS binding to rat cerebral cortical membranes. PAM: glutamate, DCG-IV, LCCG-I and LY379268 stimulated [³⁵S]GTPγS binding and glutamate mediated iCa²⁺; [³H]DCG-IV binding to human mGlu₂. NAL: [³H]LY341495 binding to human mGlu₂.	Schaffhauser et al., 2003; Hemstapat et al., 2007; Odagaki et al., 2011, 2013; Lavreysen et al., 2013
MNI-137	2/3	mGlu₂ NAM: glutamate and DCG-IV mediated iCa²⁺ and glutamate stimulated [³⁵S]GTPγS binding. mGlu₃ NAM: glutamate mediated iCa²⁺ and [³⁵S]GTPγS binding. mGlu₂ NAL: [³H]LY341495 binding and glutamate affinity.	Hemstapat et al., 2007; Yin et al., 2014;
RO4491533	2/3	mGlu₂ NAM: [³H]LY354740 affinity; ACPD inhibition of cAMP accumulation; glutamate stimulation of GIRK channels and [³⁵S]GTPγS binding. mGlu₂ NAL: [³H]LY341495 binding to human mGlu₂. mGlu₃ NAM: glutamate stimulation of GIRK channels.	Campo et al., 2011; Woltering et al., 2010
RO4988546	2/3	mGlu₂ NAM: [³H]LY354740 binding; LY354740 stimulation of [³⁵S]GTPγS binding and iCa²⁺. mGlu₂ NAL: [³H]HYDIA binding.	Lundstrom et al., 2011
RO5488608	2/3	mGlu₂ NAM: [³H]LY354740 binding; LY354740 stimulation of [³⁵S]GTPγS binding and iCa²⁺. mGlu₂ NAL: [³H]HYDIA binding.	Lundstrom et al., 2011

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ACPD, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid; BINA, biphenyl-indanone A; CBiPES, N-(4′-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride; DCG-IV, (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine; GIRK, G protein–coupled inwardly rectifying potassium channel; HYDIA, (1S,2R,3R,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid; L-CCG-I, (2S,1′S,2′S)-2-(carboxycyclopropyl)glycine; LY2607540, THIIC, N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide; LY354740, (1S,2R,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid; LY487379, 2,2,2-trifluoro-N-[4-(2-methoxyphenoxy)phenyl]-N-(pyridin-3-ylmethyl)ethanesulfonamide; MNI-137, 4-(8-bromo-5-oxo-3,4,5,6-tetrahydro-1,6-benzodiazocin-2-yl)pyridine-2-carbonitrile; NAL, neutral allosteric ligand; RO4491533, 4-[3-(2,6-dimethylpyridin-4-yl)phenyl]-7-methyl-8-(trifluoromethyl)-1,3-dihydro-1,5-benzodiazepin-2-one; RO4988546, 5-[7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-ylethynyl]-pyridine-3-sulphonic acid; RO5488608, 3′-(8-methyl-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-biphenyl-3-sulphonic acid.

TABLE 3.

Molecular pharmacology of selected allosteric ligands for group III metabotropic glutamate receptors

Ligand/Selectivity		Allosteric Pharmacology	References
ADX71743	7	NAM: L-AP4 efficacy for iCa²⁺ and inhibition of cAMP accumulation; glutamate in mediating inhibition of cAMP accumulation.	Kalinichev et al., 2013
AMN082	7^#	NAL-agonist: inhibition of cAMP accumulation, stimulates pERK1/2 and receptor internalization. NAL: MSOP (does not block AMN082 internalization).	Mitsukawa et al., 2005; Pelkey et al., 2007; Suzuki et al., 2007; Iacovelli et al., 2014
AZ12216052	8	PAM-agonist: glutamate stimulation of [³⁵S]GTPγS binding.	Duvoisin et al., 2010
MMPIP	7	NAM: L-AP4 efficacy for iCa²⁺ and changes in cell mass distribution; L-CCG-I and CPPG efficacy for iCa²⁺; glutamate stimulation of GIRK channels. Inverse/agonist: cAMP accumulation and Epic label-free assay. NAL: [³H]LY341495 binding.	Suzuki et al., 2007; Niswender et al., 2010
PHCCC	4/6	PAM: glutamate for iCa²⁺ and GIRK channel activation; L-AP4 stimulated iCa²⁺ and changes in VFT. PAM-agonist: L-AP4 and glutamate stimulated [³⁵S]GTPγS binding. mGlu₁ NAM: glutamate mediated iCa²⁺. mGlu₆ agonist: glutamate mediated calcium current inhibition.	Maj et al., 2003; Marino et al., 2003; Beqollari and Kammermeier, 2008; Niswender et al., 2008; Yin et al., 2014; Rovira et al., 2015
VU0155041	4	PAM-agonist: glutamate mediated iCa²⁺and GIRK channel activation. PAM: L-AP4 mediated iCa²⁺and changes in VFT.	Niswender et al., 2008; Yin et al., 2013; Rovira et al., 2015
VU0155094	4-8	PAM: glutamate apparent affinity (mGlu_{4, 7, 8}); glutamate efficacy for stimulation of GIRK channels (mGlu₈) and iCa²⁺ (mGlu_4,7); L-AP4 apparent affinity (mGlu_{7, 8}); L-AP4 efficacy for iCa²⁺ (mGlu₄); LSP4-2022 apparent affinity (mGlu_{4, 7, 8}); LSP4-2022 efficacy for iCa²⁺ (mGlu₄). NAL/NAM: L-AP4 apparent affinity (mGlu₄); L-AP4 and LSP4-2022 efficacy for iCa²⁺ (mGlu₇). NAL: glutamate, L-AP4, LSP4-2022 efficacy for iCa²⁺ (mGlu₈).	Jalan-Sakrikar et al., 2014
VU0422288	4-8	PAM: glutamate, L-AP4 and LSP4-2022 efficacy for iCa²⁺and GIRK channel activation (mGlu_4,7,8); glutamate, L-AP4, LSP4-2022 apparent affinity (mGlu_7,8). NAL: glutamate apparent affinity (mGlu₄). NAM: L-AP4 and LSP4-2022 apparent affinity (mGlu₄).	Jalan-Sakrikar et al., 2014

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ADX71743, 6-(2,4-dimethylphenyl)-2-ethyl-4,5,6,7-tetrahydro-1,3-benzoxazol-4-one; AZ12216052, 2-{[(4-bromophenyl)methyl]sulfanyl}-N-[4-(butan-2-yl)phenyl]acetamide; CPPG, 2-amino-2-cyclopropyl-2-(4-phosphonophenyl)acetic acid; GIRK, G protein–coupled inwardly rectifying potassium channel; L-CCG-I, (2S,1′S,2′S)-2-(carboxycyclopropyl)glycine; MMPIP, 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo [4,5-c]pyridine-4(5H)-one hydrochloride; MSOP, 2-amino-2-methyl-3-phosphonooxypropanoic acid; NAL, neutral allosteric ligand.

^{^#}

Compound and/or its metabolite hits other non-mGlu targets (Ayala et al., 2008; Sukoff Rizzo et al., 2011).

Complexities of mGlu Receptor Allosteric Modulator Pharmacology

Stimulus-Bias.

Despite definite success in the discovery of mGlu allosteric ligands, the pharmacology of allosteric modulators is inherently more complex than their orthosteric counterparts. The overall pharmacological effect of an allosteric ligand includes affinity and efficacy as well as the cooperativity between the allosteric and orthosteric ligands. With respect to ligand efficacy it has become increasingly accepted that occupancy and efficacy are not necessarily linearly linked. The concept that orthosteric ligands may differentially impact the G protein coupling and other functional responses mediated by activation of the receptor has come to the fore in recent years (Fig. 1). This phenomenon referred to as “stimulus-bias” (although it has had many other monikers including “agonist-directed trafficking of receptor stimulus,” “functional selectivity,” and “biased agonism”) has now been observed for many GPCRs, including mGlu₁, mGlu₄, mGlu₇, and mGlu₈ (Emery et al., 2012; Gregory et al., 2012; Jalan-Sakrikar et al., 2014). For example, stimulus-bias is evident when comparing orthosteric agonists L-AP4 [l-2-amino-4-phosphonobutyrate] and LSP4-2022 [(2S)-2-amino-4-([[4-(carboxymethoxy)phenyl](hydroxy)methyl](hydroxy)phosphoryl)butanoic acid] with glutamate between Ca²⁺ mobilization and G protein–coupled inwardly rectifying potassium channel activation at a single group III subtype (Jalan-Sakrikar et al., 2014). Interestingly, when these orthosteric agonist bias profiles are compared between mGlu₇ and either mGlu₄ or mGlu₈, there is a complete reversal in the direction of bias for the same ligands across the same two pathways. This finding highlights the important concept that the endogenous ligand itself will have a “natural bias,” revealed in this study by differences between different group III mGlu subtypes. Stimulus-bias is thought to arise from ligands stabilizing different complements of receptor conformations that favor one suite of receptor activation outcomes over others. It is perhaps not surprising then that there is preliminary evidence for stimulus-bias when comparing allosteric agonist activity to that with glutamate. For example, VU29 [N-(1,3-diphenyl-1H-pyrazolo-5-yl)-4-nitrobenzamide] and CDPPB [3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide] are PAM-agonists of mGlu₅ for both intracellular Ca²⁺ mobilization and phosphorylated extracellular-signal regulated kinases 1 and 2 (pERK1/2) and notably have higher intrinsic efficacy for pERK1/2 relative to Ca²⁺ signaling (Gregory et al., 2012). Glutamate, however, shows the reverse, with higher efficacy for Ca²⁺ signaling over pERK1/2. Similar observations have been reported for mGlu₁ PAM-agonists relative to glutamate between Ca²⁺ mobilization and cAMP accumulation (Sheffler and Conn, 2008). Moreover, many of the mGlu₅ PAM-agonists for pERK1/2 are super-agonists, capable of achieving higher maximal responses than glutamate (Gregory et al., 2012). Although it should be noted that both ligand and system kinetics may contribute to these observations of biased agonism. Negative allosteric modulators are also often reported to be inverse agonists (Tables 1, 2, and 3); however, these observations are assay dependent, likely a result of receptor constitutive activity and assay resolution. Comprehensive investigation into stimulus-bias that factors in these contributing mechanisms and confounds is sorely needed.

Fig. 1. — Schematic depicting the concepts of biased agonism and modulation. (A) The endogenous ligand (blue triangle) activates the receptor, resulting in intracellular signal transduction. However, not all pathways will be activated to the same extent; this is the natural bias of the receptor/system. (B) A surrogate orthosteric agonist (red triangle) may engender a different suite of active receptor conformations, resulting in biased signaling compared with the endogenous ligand; in this case the strength of signaling to response 1 versus 2 is reversed. (C) The binding of an allosteric modulator (orange star) potentiates the response to the endogenous agonist for all signal pathways to the same extent. (D) In contrast, a biased allosteric modulator (purple star) may have different magnitude or direction on cooperativity depending on the response measured; in this case, response 1 is potentiated whereas response 2 is inhibited.

An additional mechanism that may also contribute to observations of stimulus-bias relates to receptor compartmentalization. For example, a large pool of intracellular mGlu₅ is located on the nuclear membrane (Jong et al., 2005; Kumar et al., 2008). Activation of mGlu₅ at the cell surface versus the nuclear membrane results in the activation of different signaling cascades, as demonstrated through the use of permeable/transported and impermeable/nontransported orthosteric and allosteric ligands of mGlu₅ (Jong et al., 2009; Kumar et al., 2012). Furthermore, activation of cell surface mGlu₅ leads to long-term potentiation and long-term depression in the hippocampus, whereas activation of intracellular mGlu₅ only mediates long-term depression (Purgert et al., 2014). These findings highlight that stimulus-bias may also arise from a differential ability of different chemotypes to access distinct subcellular compartments where receptors may be located. Therefore the lipophilicity or transportability of an allosteric ligand may impact the overall functional outcome observed.

Biased Modulation.

A related concept to biased agonism is the phenomenon of biased modulation (Fig. 1), if we consider that the conformations engendered by the simultaneous occupation of a receptor with an orthosteric and allosteric ligand that give rise to cooperativity differ from those engendered by binding of orthosteric ligand alone. Therefore this raises the possibility that the “natural bias” of an endogenous ligand may be influenced by an allosteric modulator. Conceptually, this may manifest as a change in the magnitude and/or direction of the cooperativity factors that describe the allosteric interaction depending on the receptor activation outcome measured. Alternatively, allosteric modulators may also show differential apparent affinity estimates depending upon the receptor activation outcome measured. In recent years, there have been a growing number of reports of biased mGlu allosteric modulation. For example at mGlu₅, CPPHA [N-(4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl)-2-hydroxybenzamide], and DFB [((3-fluorophenyl)methylene)hydrazone-3-fluorobenzaldehyde] are both PAMs for glutamate-mediated Ca²⁺ mobilization in rat cortical astrocytes; however, DFB potentiates, whereas CPPHA inhibits DHPG [3,5-dihydroxyphenylglycine]-stimulated pERK1/2 (Zhang et al., 2005). Furthermore, multiple mGlu₅ modulators have lower positive cooperativity for glutamate-mediated pERK1/2 versus intracellular Ca²⁺ mobilization (Gregory et al., 2012). Recent studies suggest that biased modulation has relevance in more physiologic systems, raising the possibility that biased modulation may have clinical implications. For example, a novel mGlu₅ selective modulator from the same chemotype as CPPHA, NCFP [N-(4-chloro-2-[(1,3-dioxoisoindolin-2-yl)methyl)phenyl)picolinamide], potentiated DHPG-induced depolarization of subthalamic nucleus neurons but lacked the ability to potentiate induction of long-term potentiation or long-term depression in the hippocampus (Noetzel et al., 2013). Importantly, another mGlu₅ allosteric modulator, VU0092273 [3′-(8-methyl-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-biphenyl-3-sulfonic acid], that shared a similar pharmacological mGlu₅ PAM profile in recombinant cells, potentiated all three slice electrophysiological responses (Noetzel et al., 2013), suggesting that NCFP is showing true biased modulation in a native environment. Another novel mGlu₅ allosteric modulator, VU0409551 [5-[(4-fluorophenyl)carbonyl]-2-(phenoxymethyl)-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridine], was recently disclosed that potentiates multiple glutamate-induced mGlu₅ signaling responses in cell-based assays, but has no efficacy in modulating hippocampal long-term potentiation or N-methyl-d-aspartate receptor currents (Rook et al., 2015). However, VU0409551 has efficacy in preclinical rodent models of psychosis and cognition (Rook et al., 2015), suggesting that biased allosteric modulators of mGlu₅ can possess preclinical efficacy.

Biased modulation is not limited to mGlu₅ PAMs, both positive and negative modulators of group III receptors have been suggested to induce biased receptor signaling (Niswender et al., 2010; Jalan-Sakrikar et al., 2014). The extent and prevalence of biased modulators is likely to be highly underappreciated. This is due to the fact that the vast majority of mGlu allosteric modulators are characterized in a single cell-based assay, generally Ca²⁺ mobilization, to classify and rank compounds on the basis of potency. Furthermore, the therapeutic relevance of biased pharmacology has yet to be realized; however, it is tempting to speculate that unappreciated bias may contribute to differential efficacy of allosteric modulators in behavioral models. For example, 1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((4-fluorobenzyl)oxy)ethanone, an mGlu₅ PAM of glutamate, requires far lower doses for efficacy in cognitive models compared with reversing amphetamine-induced hyperlocomotion, a model for antipsychotic efficacy (Gregory et al., 2013a). Moreover, there is the potential that biased modulation may be exploited to develop therapeutics that are not only subtype selective but also pathway selective, modulating receptor responses that yield therapeutic effects and avoiding those that give rise to on-target adverse effects.

Probe Dependence.

A related phenomenon to biased modulation is that of probe dependence, where allosteric interactions are dependent upon the chemical nature of the two ligands under investigation. The result being that the direction and/or magnitude of cooperativity may be significantly different. There are multiple examples of probe dependence at the group II mGlu receptors. Biphenyl-indanone A potentiates Ca²⁺ oscillations in cortical neurons induced by the mGlu₂ selective orthosteric agonist LY541850 [(1S,2S,4R,5R,6S)-2-amino-4-methylbicyclo[3.1.0]hexane2,6-dicarboxylic acid] but not the mixed group II orthosteric agonist LY379268 [(−)-2-oxa-4-minobicyclo[3.1.0]hexane-4,6-dicarboxylate] (Sanger et al., 2013). JNJ-40068782 [3-cyano-1-cyclo-propylmethyl-4-(4-phenyl-piperidin-1-yl)-pyridine-2(1H)-one], a PAM-agonist of glutamate-stimulation of [³⁵S]GTPγS binding and Ca²⁺ mobilization at mGlu₂, has neutral cooperativity with the orthosteric antagonist radioligand [³H]LY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid] and positive cooperativity with the orthosteric agonist radioligand [³H]DCG-IV [(2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine] (Lavreysen et al., 2013). For group I and III mGlu receptors, there are also select examples of probe dependence. Affinity modulation occurs between the orthosteric agonist quisqualate and mGlu₅ PAMs (Bradley et al., 2011); however, a separate study found no evidence for affinity modulation (i.e., neutral cooperativity) between glutamate and mGlu₅ PAMs of glutamate in functional assays (Gregory et al., 2012). At mGlu₄ and mGlu₇, VU0155094 [methyl 4-(3-(2-((4-acetamidophenyl)thio)acetyl)-2,5-dimethyl-1H-pyrrol-1-yl)benzoate] and VU0422288 [N-(3-chloro-4-((5-chloropyridin-2-yl)oxy)phenyl)picolinamide] have different degrees of cooperativity depending upon both the orthosteric agonist and the assay endpoint used (Jalan-Sakrikar et al., 2014). For example, at mGlu₇, VU0155094 is neutral with respect to the apparent affinity of LSP4-2022 and L-AP4 but a positive modulator of glutamate apparent affinity (Jalan-Sakrikar et al., 2014). Clearly, probe dependence is evident for the mGlu family and should be taken into consideration when designing screening paradigms and characterizing mGlu allosteric modulators. The choice of assay and/or probe can result in a very different pharmacological profile. This is of particular importance for mGlu₇ where L-AP4 is most commonly used as the orthosteric agonist given the low affinity of this subtype for glutamate (in the millimolar range). Moreover, extracellular Ca²⁺ ions can activate mGlu₁, influencing the responses to orthosteric agonists, indicating that two endogenous orthosteric agonists need to be considered with respect to probe dependence but also that different endogenous ligands can allosterically interact at mGlu₁ (Jiang et al., 2014). Importantly, extracellular Ca²⁺ activation of mGlu₁ can be modulated by small molecule positive and negative allosteric modulators of glutamate (Ro67-4853 [butyl (9H-xanthene-9-carbonyl)carbamate] and CPCCOEt) (Jiang et al., 2014). Probe dependence can also be an important consideration when assessing allosteric modulators in native systems (brain slice electrophysiology or primary neuronal cultures) where surrogate agonists are typically used to selectively activate a particular mGlu subtype and avoid the confounds of glutamate activating ionotropic glutamate receptors and being subject to endogenous transporters.

Protein-Protein Interactions.

Another important consideration in assessing allosteric modulator pharmacology in native systems is the fact that the mGlu family are obligate dimers (El-Moustaine et al., 2012) that also have the capacity to form heteromers with other subtypes (Doumazane et al., 2011; Kammermeier, 2012; Sevastyanova and Kammermeier, 2014; Yin et al., 2014) as well as with other unrelated GPCRs (Gama et al., 2001; Gonzalez-Maeso et al., 2008; Cabello et al., 2009). Unsurprisingly, such complexity in receptor configurations can influence the pharmacology of small molecules. Heterodimerization of mGlu₄ and mGlu₂ has differential effects on the pharmacology of different allosteric ligands (Kammermeier, 2012; Yin et al., 2014). For example, at the mGlu_2/4 heteromer PHCCC [N-phenyl-7-(hydroxyimino)cyclopropa[b] chromen-1a-carboxamide] has lower cooperativity with L-AP4, whereas Lu AF21934 [(1S,2R)-2-[(aminooxy)methyl]-N-(3,4-dichlorophenyl)cyclohexane-1-carboxamide] and VU0155041 [(1R,2S)-2-[(3,5-dichlorophenyl)carbamoyl]cyclohexane-1-carboxylic acid] have decreased affinity but higher cooperativity compared with mGlu₄ homodimers (Yin et al., 2014). This perturbation in the pharmacology of allosteric ligands has consequences in vivo at synapses where mGlu₂ and mGlu₄ are coexpressed. VU0155041 and Lu AF21934 are both effective at potentiating the actions of L-AP4 at corticostriatal synapses (Gubellini et al., 2001; Yin et al., 2014). However, PHCCC does not potentiate the actions of L-AP4 at corticostriatal synapses (Yin et al., 2014), despite being an efficacious mGlu₄ PAM of L-AP4–induced responses at other synapses (Marino et al., 2003; Valenti et al., 2005; Jones et al., 2008). Direct protein-protein interactions are not necessarily required for a coexpressed receptor to impact the pharmacological effect of an mGlu ligand. Coexpression and coactivation of G_q-coupled receptors enhances mGlu₄ stimulus-response coupling to orthosteric and allosteric agonists in intracellular Ca²⁺ mobilization but not cAMP accumulation assays (Yin et al., 2013). It is apparent that cellular context, measure of receptor function and coexpression of other GPCRs can impact the pharmacology of small molecule allosteric ligands, leading to unanticipated consequences in native systems. However, this complexity extends further to the structure-activity relationships of allosteric modulators themselves.

Molecular Switches.

Given the complexities of allosteric modulation surrounding stimulus-bias and probe dependence it is perhaps not surprising that structure-activity relationships (SAR) for mGlu receptor allosteric modulators are notoriously challenging. SAR is often reported to be “steep,” with minimal changes resulting in a complete loss of activity (Conn et al., 2014; Lindsley, 2014). In addition, mGlu allosteric chemotypes often show “molecular switches” where the same scaffold can give rise to modulators with negative, positive, and neutral cooperativity with the same orthosteric agonist (Wood et al., 2011). The phenomenon was first observed during the development of DFB, an mGlu₅ PAM for glutamate-mediated intracellular Ca²⁺ mobilization (O'Brien et al., 2003). Recently, this propensity for molecular switching was exploited with the development of a photoswitchable allosteric modulator for mGlu₅, where negative cooperativity with glutamate could be controlled by exposure to different light wavelengths (Pittolo et al., 2014). However, unexpected changes in cooperativity continue to be a challenge for medicinal chemistry programs and interpretation of SAR (Hammer et al., 1980; Sharma et al., 2009; Rodriguez et al., 2010; Schann et al., 2010; Zhou et al., 2010; Lamb et al., 2011; Sams et al., 2011; Sheffler et al., 2012). These difficulties in SAR interpretation can in part be attributed to a paucity in our understanding of the structural basis of allosterism. The majority of discovery programs rely on modulator potency curves in the presence of a single concentration of agonist to classify allosteric ligands as active/inactive and ascribe either positive or negative cooperativity. However, potency represents a composite measure of efficacy, affinity, and cooperativity (Gregory et al., 2012). As such, modifications to a chemotype may influence any one of these three parameters. Therefore, more quantitative analysis of allosteric chemotypes is required to truly understand how SAR relates to efficacy, affinity, and cooperativity. Going forward a key challenge will be coupling SAR interpretation as we improve our understanding of the structural basis of allosterism.

Structural Basis of Allosteric Modulation

The mGlus are family C GPCRs typified by their large extracellular N-terminal Venus flytrap domain (VFT), linked via a cysteine-rich domain to the seven transmembrane (TM) spanning α-helical domains that are the hallmark of the GPCR superfamily. The orthosteric site is located in the N-terminal domain and to date all small molecule allosteric modulators are thought to bind within the 7TMs. Historically, receptor chimeras proved valuable to (1) definitively demonstrate an allosteric mechanism of action for small molecule ligands and (2) to localize allosteric binding sites to the 7TM domains. Chimeric constructs swapping the VFT of one subtype onto another or even exchanging with non-mGlu family C GPCRs have been used. Chimeras between mGlu₁ and mGlu₅ or mGlu₄ and the calcium-sensing receptor were used to validate the allosteric mechanism of action of mGlu₁ selective allosteric modulator CPCCOEt (Brauner-Osborne et al., 1999; Litschig et al., 1999; Gasparini et al., 2001). Subsequent studies used mGlu_1/5 chimeras to demonstrate MPEP (2-methyl-6-(phenylethynyl)pyridine; an mGlu₅ selective NAM), and multiple mGlu₁ PAMs recognized an overlapping binding site with that of CPCCOEt (Pagano et al., 2000; Knoflach et al., 2001). Chimeric constructs were also used to validate an allosteric mechanism of action for PHCCC, AMN082 [N,N′-dibenzhydrylethane-1,2-diamine dihydrochloride], and BAY36-7620 [(3aS,6aS)-hexahydro-5-methylene-6a-(2-naphthalenylmethyl)-1H-cyclopenta[c]furan-1-one] at mGlu₄, mGlu₇, and mGlu₁, respectively (Carroll et al., 2001; Maj et al., 2003; Mitsukawa et al., 2005). Another approach to achieve gross localization of allosteric binding sites is through the generation of N-terminal truncated receptors. The extracellular VFT can be removed to generate a “headless” mGlu, yielding a receptor construct that does not respond to glutamate but can couple to intracellular signaling pathways (Goudet et al., 2004). Headless mGlu₁ and mGlu₅ are constitutively active such that negative allosteric modulators behave as inverse agonists (Goudet et al., 2004; Chen et al., 2007; Suzuki et al., 2007). Furthermore, headless mGlu₅ can be stimulated by small molecule positive allosteric modulators that do not necessarily have intrinsic efficacy at the full-length receptor (Chen et al., 2007; Goudet et al., 2004; Noetzel et al., 2013). Interestingly, NCFP had little or no efficacy for stimulating headless mGlu₅, despite having a similar magnitude of positive cooperativity as VU0092273, which can activate headless mGlu₅ (Noetzel et al., 2013). The headless mGlu 7TM is thought to behave as a monomer (Goudet et al., 2004), so perhaps this discrepancy relates to receptor dimerization in the full-length receptor being important either for NCFP binding or cooperativity.

Two recent X-ray crystal structures were solved for the 7TMs of group I mGlus with allosteric modulators bound [PDB IDs 4OO9 and 4OR2 (Dore et al., 2014; Wu et al., 2014)]. Before this, researchers relied on family A 7TM templates to perform homology modeling and interpret site-directed mutagenesis data. Despite low sequence homology (<20%), these approaches proved fruitful, localizing allosteric binding pockets of mGlu₁, mGlu_2, mGlu₄, and mGlu₅ to a region analogous to that of the biogenic amine binding sites in family A GPCRs (Ott et al., 2000; Pagano et al., 2000; Malherbe et al., 2003a,b; Lundstrom et al., 2011; Molck et al., 2012; Gregory et al., 2013b, 2014; Rovira et al., 2015). In light of the new crystal structures, although alignments and secondary structure predictions of TMs 5–7 deviated from that observed in the mGlu₁ and mGlu₅ structures, the general localization of the pocket was consistent with earlier reports. Many residues that had previously been identified in mutagenesis-based studies were recapitulated in the crystal structures (discussed in detail below). Ongoing research continues to refine our understanding of binding pocket(s) within the 7TM bundle in particular in relation to determinants that govern selectivity, affinity, cooperativity, and efficacy of allosteric modulators.

The Common mGlu Allosteric Site

The concept for a common allosteric site between mGlu subtypes arises from three lines of evidence: (1) allosteric modulators that lack subtype selectivity; (2) competitive interactions between diverse chemotypes and allosteric radioligands; (3) overlapping binding pockets based on mutagenesis studies and observed in X-ray crystal structures. Although attaining selectivity with allosteric modulators is considerably more effective than for orthosteric ligands, there are a number of examples of allosteric modulators that have efficacy at multiple subtypes. MPEP is both a negative allosteric modulator of glutamate at mGlu₅ and a positive allosteric modulator of L-AP4 at mGlu₄ (Mathiesen et al., 2003). Conversely, DFB and CPPHA, which potentiate glutamate signaling at mGlu₅ are weak negative allosteric modulators of glutamate at mGlu₄ and mGlu₈ (O'Brien et al., 2003, 2004). In addition, PHCCC, an mGlu₄ PAM for glutamate and L-AP4, negatively modulates glutamate at mGlu₁ (Annoura et al., 1996; Maj et al., 2003). The recent report of a molecular switch to mGlu₃ NAM from an mGlu₅ PAM scaffold (Sheffler et al., 2012) reveals that the subtleties of interactions within this common pocket that dictate subtype selectivity are not limited to crossover between group I and group III mGlu receptors alone. This lack of selectivity within the common binding pocket is also associated with differential cooperativity between subtypes, highlighting that the small molecule interactions within the common allosteric site can elicit either positive or negative cooperativity.

Identification of allosteric ligands that interact with this common mGlu allosteric site has been facilitated by the development of radiolabeled mGlu allosteric modulators. Multiple selective tritiated and positron emission tomography (PET) allosteric ligands have been developed for mGlu₁, mGlu₂, and mGlu₅ (Anderson et al., 2002, 2003; Gasparini et al., 2002; Cosford et al., 2003b; Lavreysen et al., 2003; Kohara et al., 2005; Malherbe et al., 2006; Ametamey et al., 2007; Treyer et al., 2007; Baumann et al., 2010). Through the use of inhibition binding assays with these allosteric ligands a direct assessment of competitive versus noncompetitive binding modes can be performed (Lavreysen et al., 2003, 2004; Kinney et al., 2005; Malherbe et al., 2006; Hemstapat et al., 2006; Chen et al., 2007; Lundstrom et al., 2011). Such experiments are often the first step toward identifying allosteric modulators that bind to alternative allosteric sites [(Chen et al., 2008; Hammond et al., 2010) discussed in further detail later]. However, competition binding experiments may also be used to identify neutral allosteric ligands that interact with the common allosteric site but have neutral cooperativity with agonist(s) in functional screening assays (Rodriguez et al., 2005; Sams et al., 2011).

Early mutational studies investigating group I mGlu receptor allosteric binding pockets exploited nonconserved residues within the 7TMs. Substitution of mGlu₁ nonconserved amino acids onto the equivalent positions in mGlu₅, and vice versa, resulted in gain-of-function of selective allosteric modulators (Litschig et al., 1999; Pagano et al., 2000; Knoflach et al., 2001; Goudet et al., 2005; Surin et al., 2007). These mutagenesis studies pointed to a common location for allosteric binding pockets for group I mGlu receptors. Additional studies have shown that residues at positions 3.40 and 7.38 are important for allosteric modulation of both mGlu₁ and mGlu₅ [Ballesteros-Weinstein numbering (Ballesteros and Weinstein, 1995) adopted from mGlu₁ structural alignment to family A GPCRs; Malherbe et al., 2003a,b, 2006; Muhlemann et al., 2006; Suzuki et al., 2007; Fukuda et al., 2009; Gregory et al., 2012, 2013b, 2014; Turlington et al., 2014; Wu et al., 2014]. Subsequently, key residues for the potency and/or binding of mGlu₁, mGlu₂, mGlu₄, and mGlu₅ allosteric modulators from diverse chemical scaffolds have been mapped to TMs 3–7. Across the four subtypes multiple residues have repeatedly been reported as contributing to allosteric modulation. For all four subtypes, residues in positions 3.36, 5.43, and 6.48 are crucial for both positive and negative allosteric modulators (Pagano et al., 2000; Malherbe et al., 2003a, 2006; Muhlemann et al., 2006; Fukuda et al., 2009; Lundstrom et al., 2011; Gregory et al., 2012, 2013b, 2014; Molck et al., 2012; Turlington et al., 2014; Wu et al., 2014; Rovira et al., 2015). Position 7.45 has also been implicated in mGlu₄ and mGlu₅ allosteric modulation (Molck et al., 2012; Gregory et al., 2013b, 2014; Turlington et al., 2014; Rovira et al., 2015); there are no reports investigating the influence of this amino acid on selective allosteric modulators of mGlu₁ or mGlu₂. Between group I mGlu receptors and mGlu₂, three residues are common: 5.44, 5.47, and 6.55 (Knoflach et al., 2001; Malherbe et al., 2003b, 2006; Schaffhauser et al., 2003; Hemstapat et al., 2006; Muhlemann et al., 2006; Rowe et al., 2008; Fukuda et al., 2009; Lundstrom et al., 2011; Gregory et al., 2012, 2013b, 2014; Molck et al., 2012). Group 1 receptors and mGlu₄ share a common determinant in F6.51 (Malherbe et al., 2003a,b, 2006; Muhlemann et al., 2006; Suzuki et al., 2007; Fukuda et al., 2009; Gregory et al., 2014; Rovira et al., 2015). Two residues at the top of TM3 (3.28 and 3.29) are important for allosteric modulation of both mGlu₂ and mGlu₄ (Lundstrom et al., 2011; Rovira et al., 2015), with position 3.29 also implicated in the activity of some mGlu₅ allosteric modulators (Malherbe et al., 2003b, 2006; Molck et al., 2012). Therefore these mutagenesis data reinforce the notion of overlapping binding pockets across the mGlu family.

Comparison of the recently solved mGlu₁ and mGlu₅ crystal structures reveals a similar architecture for the backbone of the transmembrane-spanning helices (Fig. 2A). Overlay of the 7TM binding pockets for FITM [4-fluoro-N-(4-(6-(isopropylamino)pyrimidin-4-yl)thiazole-2-yl)-N-methylbenzamide] and mavoglurant in mGlu₁ and mGlu₅, respectively, confirmed that these subtypes have overlapping allosteric binding pockets within the 7TMs (Dore et al., 2014; Wu et al., 2014). Examination of binding pockets for mavoglurant and FITM reveals that mavoglurant binds deeper within the 7TM bundle (Fig. 2B). Side chain conformations of two key nonconserved residues in TM3 of mGlu₅: P655^3.36 and S658^3.39 (mGlu₁ equivalents are S668 and C671, respectively) create greater space within the pocket that allows mavoglurant to bind deeper within the 7TM bundle (Fig. 2C). These crystal structures of closely related mGlu receptors have yielded structural insights with respect to how selectivity can be achieved in the common mGlu allosteric site.

Fig. 2. — Comparison of allosteric pockets within the 7TM domains of mGlu₁ and mGlu₅. (A) X-ray crystal structures of 7TMs of mGlu₅ (gray, PDB ID 4OO9) and mGlu₁ (teal; PDB ID 4OR2) were aligned using MacPyMOL (The PyMOL Molecular Graphics System, Version 1.3, Schrödinger, LLC, New York, NY). (B) Inside surface rendering of the allosteric binding pockets of mavoglurant (black) in mGlu₅ (gray) and FITM (blue) in mGlu₁ (teal). (C) Zoomed in image of the bottom of the allosteric pockets with mavoglurant shown. Two amino acids differ between mGlu₁ and mGlu₅ in this region, the differences in the side chains (depicted as sticks) create more space in mGlu₅, allowing mavoglurant to bind deeper within the 7TM bundle. All images created using MacPyMOL.

Delineating Affinity versus Cooperativity Determinants

The vast majority of research on allosteric modulator SAR and structure-function has relied on measures of allosteric modulator potency; however, potency values represent a composite of affinity and cooperativity. In recent years the application of rigorous analytical pharmacological methods has facilitated delineation of the impact of mutations on allosteric modulator affinity, cooperativity, and efficacy based on functional interaction data alone. By combining this research with earlier studies using radiolabeled allosteric modulators where affinity was determined or a loss of binding was observed we can start to map affinity determinants in the binding pocket. Residues known to be crucial affinity determinants are summarized in Table 4 (also see Supplemental Table 1) where the most well characterized representatives from individual allosteric modulator scaffolds were included. These affinity determinants are also mapped onto the mGlu₁ and mGlu₅ structures (Fig. 3, A and B). Significant overlap is observed between mGlu₁ and mGlu₅, although there is limited affinity data for mGlu₁. For mGlu₅, six residues have been implicated in the binding of most PAMs and NAMs: P655^3.36, Y659^3.40, T781^6.44, W785^6.48, S809^7.45, and A810^7.46 within the common allosteric site. Mapping the known affinity determinants for MPEP, the most well studied mGlu₅ allosteric ligand with respect to structure-function, onto the mGlu₅ crystal structure yields additional insights (Fig. 4; Pagano et al., 2000; Malherbe et al., 2003b; Gregory et al., 2012, 2013b, 2014). Coloring residues on the basis of the impact of mutations reveals that substitutions that cause a moderate (<10-fold) reduction in affinity are located on the fringes of the mavoglurant binding pocket or are immediately adjacent to key residues (Fig. 4; Supplemental Table 1).

TABLE 4.

Known affinity determinants for mGlu allosteric modulators interacting with the common allosteric site.

Most well characterized representatives from individual allosteric modulator scaffolds were selected for inclusion. Alignment of amino acids and assignment of Ballesteros-Weinstein numbering was adopted from the structural alignment to class A GPCRs in Wu et al., 2014. A colorized version of this table (Supplemental Table 1) is included in the online supplemental materials.

Ligand/Subtype		Amino Acid Residue Position
		3.29	3.36	3.39	3.40	5.43	5.44	5.47	5.48	6.44	6.48	6.51	6.52	6.55	6.56	7.38	7.45		7.46
EM-TBPC	1				Y		V/L				W+	F	–	Y		T
FITM	1		s			P				–						T	–
MPEP	5	R	P	S	Y	P	L	–	G	T	W	F	V	Y	f+	–	S		A
Fenobam	5	R	P	S	Y					T	W	F		Y					A
VU0366248	5		P	S	Y			N	–	t	W	f^#	–	Y	–		S	S+	A
VU0285683	5		p^#		Y	–		N	–	T	W	F	–	Y			S		A
VU0366058	5		p^#		Y			–	g+		W	F+	v+	Y+			s		A
VU0409106	5		p^#		Y			N	–	T	W	F	–	Y	f		S		A
DPFE	5	–	P		Y	P	L+		–	T	W	–	V+	y+	f+		s		A
VU29	5	–	p^#		–	p	l		G	T	w+	f	v	y	f+		–		A
VU0403602	5	–	P	s	Y^#	p	–	–		T	W		–				S		A

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DPFE, 1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((4-fluorobenzyl)oxy)ethanone; EM-TBPC, 1-ethyl-2-methyl-6-oxo-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)-1,6-dihydropyrimidine-5-carbonitrile; VU0285683, 3-fluoro-5-(3-pyridin-2-yl-1,2,4-oxadiazol-5-yl)benzonitrile; VU0366058, 2-[(1,3-benzoxazol-2-yl)amino]-4-(4-fluorophenyl)pyrimidine-5-carbonitrile; VU0403602, N-cyclobutyl-5-((3-fluorophenyl)ethynyl)picolinamide.

Lower case, mutations caused a change (2- to 10-fold) in affinity estimates that did not reach significance (determined from either radioligand binding or from functional interactions with orthosteric agonists); upper case, mutations caused a significant change in affinity (determined from either radioligand binding or from functional interactions with orthosteric agonists; not included: T6.43 for MPEP, C7.52 for VU0403602). Grayscale: white, 3- to 10-fold change; light gray, 10- to 30-fold change; mid gray, 30- to 100-fold decrease; dark gray, >100-fold decrease or complete loss of radiolabeled allosteric modulator binding (data summarized from: Pagano et al., 2000; Malherbe et al., 2003a,b, 2006; Gregory et al., 2012, 2013b, 2014; Turlington et al., 2014; Wu et al., 2014).

^{^#}

Mutation caused a loss in allosteric modulation of orthosteric agonist functional response; impact on affinity inferred from effects across other scaffolds.

–Mutation(s) had no effect on modulator affinity (determined from either radioligand binding or from functional interactions with orthosteric agonists).

+Mutation increases modulator affinity, in all other cases mutations cause a decrease (determined from either radioligand binding or from functional interactions with orthosteric agonists).

Fig. 3. — Affinity and cooperativity determinants for allosteric modulation of metabotropic glutamate receptors. (A) X-ray crystal structure of mGlu₁ 7TMs with FITM (rendered in blue sticks) bound (PDB ID 4OR2) with known mGlu₁ allosteric ligand affinity determinants highlighted in dark blue. (B) X-ray crystal structure of mGlu₅ 7TMs with mavoglurant (rendered in black sticks) bound (PDB ID 4OO9), affinity determinants for mGlu₅ allosteric ligands are highlighted in red. (C) X-ray crystal structure of mGlu₅ and mGlu₁ 7TM domains were aligned; only the mGlu₅ structure is represented in cartoon. The binding poses of FITM and mavoglurant show the overlapping allosteric pockets of mGlu₁ and mGlu₅. Highlighted are residues that when mutated change allosteric ligand cooperativity: dark red, reduce mGlu₅ NAM cooperativity; light red, increase NAM cooperativity; orange, differential effects on NAM cooperativity; dark blue, increase PAM cooperativity; light blue, increase cooperativity of NAMs and PAMs; purple, differential effects on cooperativity of NAMs versus PAMs. (D) Structures of mGlu₁ and mGlu₅ were aligned as per (C); highlighted are residues that when mutated switch allosteric modulator cooperativity: blue, PAM to either NAM or neutral switch; red, NAM to PAM switch; purple, PAM to NAM and vice versa for NAMs. All images created using MacPyMOL.

Fig. 4. — Relative contribution of 7TM residues to the binding affinity of prototypical mGlu₅ allosteric modulator, MPEP. Known affinity determinants for MPEP are mapped onto the mGlu₅-7TM X-ray crystal structure with mavoglurant bound (PDB ID 4OO9). The relative contribution of pocket residues are color-coded with side chains rendered as sticks based on mutational data as indicated in the key. All images created using MacPyMOL

In addition to effects on affinity, molecular determinants for a large set of allosteric modulators spanning multiple scaffolds with both positive and negative cooperativity have been explored at mGlu₅. Some residues that are important for modulator affinity also contribute to cooperativity; however, there are select amino acids that only influence cooperativity (Fig. 3). Negative cooperativity with glutamate of multiple allosteric modulators at mGlu₅ is decreased at P655^3.36 mutants (Gregory et al., 2013b, 2014). Additionally mutations in TMs 3–7 [Y659^3.40, N747^5.47, T781^6.44, W785^6.48, S809^7.45 (Molck et al., 2012; Gregory et al., 2014)] reduced cooperativity for negative modulators of glutamate at mGlu₅. Notably, in mGlu₁ mutations of T794^6.44 and S822^7.45 had no effect on the interaction between glutamate and FITM (Wu et al., 2014), suggesting that the structural determinants that govern cooperativity can be subtype selective even for conserved amino acids.

Negative cooperativity with glutamate at mGlu₅ was increased for M-5MPEP [2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine] and/or VU0366248 [N-(3-chloro-2-fluorophenyl)-3-cyano-5-fluorobenzamide] when mutations were introduced to S658^3.39, P743^5.43, G748^5.48, and V789^6.52 (Gregory et al., 2014). Both M-5MPEP and VU0366248 have limited negative cooperativity at the wild-type receptor, with saturating concentrations unable to completely abolish the glutamate response (Rodriguez et al., 2005; Felts et al., 2010). The cooperativity of other mGlu₅-negative allosteric modulators tested at these mutations was not discernibly different to wild type (Gregory et al., 2014). However, given that these all have strong negative cooperativity at wild type, fully abolishing the maximal glutamate response, further increases in negative cooperativity were likely beyond the limits of detection. For P743^5.43 this increase is opposite to that observed for the equivalent mGlu₁ mutation (Wu et al., 2014), again highlighting the subtype selective nature of cooperativity. Interestingly, two point mutations (N747^5.47 and S809^7.45) had differential effects on allosteric ligands, actually increasing negative cooperativity of M-5MPEP and VU0366248, respectively (Fig. 3C; Gregory et al., 2014). It is clear that the amino acids within the common allosteric site can differentially contribute to affinity and the manifestation of negative cooperativity in a manner that is very much ligand dependent.

With respect to positive allosteric modulators, no mutations have yet been demonstrated to unequivocally reduce cooperativity. However, there are multiple examples of mutations that increase the magnitude of positive cooperativity with glutamate (Fig. 3C). Shared with the low cooperativity negative modulators, mutation of P743^5.43 and V789^6.52 also increased positive cooperativity of diverse allosteric modulators with glutamate at mGlu₅ (Gregory et al., 2013b, 2014). Four residues (L744^5.44, Y792^6.55, A810^7.46, and C816^7.52) are implicated in positive but not negative cooperativity (Gregory et al., 2013b, 2014). Interestingly, compared with negative allosteric modulators, mutation of T781^6.44 and W785^6.48 had differential effects, increasing positive cooperativity with glutamate at mGlu₅ (Gregory et al., 2013b, 2014). The complicated nature of cooperativity determinants is further highlighted through evidence of mutations that engender “molecular switches” in allosteric modulator cooperativity (Fig. 3D). Substitution of Y6.51 at mGlu₅ switches DFB from a PAM of glutamate to a NAM, whereas the reverse is true for YM298198 at mGlu₁ (Muhlemann et al., 2006; Fukuda et al., 2009). Multiple additional point mutations in TMs 3, 6, and 7 can also switch acetylenic PAMs to have either neutral or negative cooperativity with glutamate at mGlu₅ (Gregory et al., 2013b; Turlington et al., 2014). Mutation of conserved W785^6.48 in mGlu₅ can switch the cooperativity of select NAMs of glutamate to positive (Gregory et al., 2014). Collectively, these data highlight the subtleties and complexities of interactions within the common allosteric site that dictate whether the binding of a ligand will result in enhancement or inhibition of mGlu receptor function. Furthermore, developing a better understanding of the dynamic ligand-receptor interactions that give rise to cooperativity will likely improve interpretation of allosteric modulator SAR and perhaps inform as to why “molecular switches” are prevalent for some chemical scaffolds.

Additional mGlu Allosteric Sites

As mentioned earlier, the development of radiolabeled allosteric ligands has identified allosteric ligands that are noncompetitive. The first such ligand identified was CPPHA, a group I mGlu selective positive allosteric modulator of glutamate. CPPHA is unable to fully displace the mGlu₅ radioligands [³H]mPEPy [3-methoxy-5-(2-pyridinylethynyl)pyridine] and [³H]MPEP or compete with [³H]R214127 [1-(3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenylethanone] for binding to mGlu₁ (O'Brien et al., 2004; Chen et al., 2008; Bradley et al., 2011; Noetzel et al., 2013). Another structurally related selective mGlu₅ PAM of glutamate, NCFP, is also thought to bind to this alternate allosteric site (Noetzel et al., 2013). Potentiation of glutamate by both NCFP and CPPHA is noncompetitively inhibited by the neutral allosteric ligand 5-methyl-2-(2-phenylethynyl)pyridine (Chen et al., 2008; Noetzel et al., 2013). This indicates that the second allosteric site is conformationally linked to the common allosteric site such that ligands binding to these sites can allosterically influence one another. Isoleucine substitution of F1.42 reduces potentiation by CPPHA (both mGlu₁ and mGlu₅) and NCFP (mGlu₅ only) (Chen et al., 2008; Noetzel et al., 2013). Interestingly, NCFP also loses either affinity or the capacity to allosterically modulate [³H]mPEPy binding and has very little efficacy as an agonist at an N-terminal truncated mGlu₅ (Noetzel et al., 2013). This suggests that the intact full-length receptor is required for this alternate allosteric site and/or receptor dimerization is also necessary. Also for mGlu₅, VU0357121 [4-butoxy-N-(2,4-difluorophenyl)benzamide] and VU0400100 [2-[2-chloro-N-methylsulfonyl-5-(trifluoromethyl)anilino]-N-(cyclopropylmethyl)acetamide] do not completely displace [³H]mPEPy binding (Hammond et al., 2010; Gregory et al., 2012; Rodriguez et al., 2012). Multiple mGlu₁ PAM scaffolds have also been flagged as binding to alternate allosteric site(s) based on no or incomplete displacement of the allosteric radioligand [³H]R214127 (Hemstapat et al., 2006). Overall, these data strongly support the hypothesis that multiple allosteric sites are present on the group I mGlu receptors.

In the absence of an allosteric radioligand, multiple allosteric sites have also been proposed for mGlu₄. The concentration-response curve for VU0155041 as an allosteric agonist at mGlu₄ was unaffected by coapplication of PHCCC, an mGlu₄ PAM of glutamate and L-AP4 (Niswender et al., 2008). Recent mutational analysis of mGlu₄ allosteric modulators suggests that these two allosteric ligands interact with the common allosteric pocket made up of TMs 3–7 but in a nonoverlapping manner (Rovira et al., 2015). Based on homology modeling and mutational data, PHCCC is proposed to bind deep within the allosteric site, analogous to the binding pose of mavoglurant in the mGlu₅ structure (Rovira et al., 2015). On the other hand, VU0155041 binds higher in the pocket, interacting with residues at the very top of the TM domains as well as extracellular loops 1 and 2 (Rovira et al., 2015). This suggests that two allosteric ligands can be accommodated simultaneously by mGlu₄; however, at least for PHCCC and VU0155041, there is neutral cooperativity between the binding of these ligands. Interestingly, VU0415374 appears to be bitopic, with homology modeling proposing it can span both binding sites. It is tempting to speculate that the reason VU0415374 has 10-fold (or more) higher apparent affinity than other mGlu₄ positive allosteric modulators is due to its ability to engage more residues within the pocket. Furthermore, it is interesting to consider that CPPHA has weak activity at mGlu₄ (Chen et al., 2008), as such there is the possibility that allosteric ligands may interact with mGlu₄ in three distinct binding modes. The extensive literature surrounding orthosteric and allosteric binding pockets of class A GPCRs may offer some insights into the location of alternative allosteric sites (Christopoulos, 2014). As confirmed in the recent cocrystal structure of the M2 muscarinic acetylcholine receptor, class A GPCR allosteric modulators recognize a binding pocket defined by the top of the TMs and the second and third extracellular loops (Kruse et al., 2013). Given the parallels between the common allosteric site of class C GPCRs and the orthosteric site in class A GPCRs, there is the possibility that alternate allosteric sites in class C GPCRs may also involve the extracellular surfaces of the receptor. Allosteric modulators that interact with different binding pockets are likely to engender a different complement of receptor conformational states than those that interact with the common allosteric site. Therefore the functional consequences of allosteric modulation through different binding pockets are likely to be divergent. Indeed, CPPHA and related compounds have biased pharmacology at mGlu₅ when compared with common site modulators (Zhang et al., 2005; Noetzel et al., 2013). We are just beginning to scratch the surface with respect to our understanding of what drives efficacy, cooperativity, and affinity through the different allosteric sites across the entire mGlu family.

Concluding Remarks

Since the discovery of the first mGlu receptor allosteric modulator in 1996, the mGlu allosteric modulator pharmacological toolbox has continued to expand with selective allosteric ligands now available for the majority of mGlu family members. This toolbox includes chemically diverse allosteric ligands that may possess positive, negative, or neutral cooperativity and/or positive or inverse agonism. At least two allosteric sites have been proposed, one of which is shared across mGlu receptor subtypes, but can still be selectively targeted. Which allosteric site is best targeted for therapeutic efficacy remains unknown. Given the complexity introduced by the phenomenon of biased modulation, the optimal allosteric ligand pharmacological profile and the relative contribution of affinity, efficacy, and cooperativity will likely be both pathophysiology and mGlu subtype dependent. With two X-ray crystal structures of the 7TMs for group I mGlu receptors now available, the field is now entering an exciting new era in our understanding of the dynamic interactions that govern allosteric ligand affinity, cooperativity, and efficacy.

Supplementary Material

Data Supplement

supp_88_1_188__index.html^{(1KB, html)}

Abbreviations

AMN082: N,N′-dibenzhydrylethane-1,2-diamine dihydrochloride
BAY36-7620: (3aS,6aS)-hexahydro-5-methylene-6a-(2-naphthalenylmethyl)-1H-cyclopenta[c]furan-1-one
CDPPB: 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide
CNS: central nervous system
CPCCOEt: 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester
CPPHA: N-(4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl)-2-hydroxybenzamide
DCG-IV: (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine
DFB: ((3-fluorophenyl)methylene)hydrazone-3-fluorobenzaldehyde
DHPG: 3,5-dihydroxyphenylglycine
FITM: 4-fluoro-N-(4-(6-(isopropylamino)pyrimidin-4-yl)thiazole-2-yl)-N-methylbenzamide
GPCR: G protein–coupled receptor
JNJ-40068782: 3-cyano-1-cyclo-propylmethyl-4-(4-phenyl-piperidin-1-yl)-pyridine-2(1H)-one
L-AP4: l-2-amino-4-phosphonobutyrate
LSP4-2022: (2S)-2-amino-4-([[4-(carboxymethoxy)phenyl](hydroxy)methyl](hydroxy)phosphoryl)butanoic acid
Lu AF21934: (1S,2R)-2-[(aminooxy)methyl]-N-(3,4-dichlorophenyl)cyclohexane-1-carboxamide
LY341495: (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid
LY379268: (−)-2-oxa-4-minobicyclo[3.1.0]hexane-4,6-dicarboxylate
LY541850: (1S,2S,4R,5R,6S)-2-amino-4-methylbicyclo[3.1.0]hexane2,6-dicarboxylic acid
mGlu: metabotropic glutamate
M-5MPEP: 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine
MPEP: 2-methyl-6-(phenylethynyl)pyridine
mPEPy: 3-methoxy-5-(2-pyridinylethynyl)pyridine
NAM: negative allosteric modulator
NCFP: N-(4-chloro-2-[(1,3-dioxoisoindolin-2-yl)methyl)phenyl)picolinamide
PAM: positive allosteric modulator
pERK1/2: phosphorylated extracellular–signal regulated kinases 1 and 2
PET: positron emission tomography
PHCCC: N-phenyl-7-(hydroxyimino)cyclopropa[b] chromen-1a-carboxamide
R214127: 1-(3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenylethanone
Ro67-4853: butyl (9H-xanthene-9-carbonyl)carbamate
SAR: structure-activity relationships
TM: transmembrane
VFT: venus flytrap domain
VU0092273: 3′-(8-methyl-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-biphenyl-3-sulfonic acid
VU0155041: (1R,2S)-2-[(3,5-dichlorophenyl)carbamoyl]cyclohexane-1-carboxylic acid
VU0155094: methyl 4-(3-(2-((4-acetamidophenyl)thio)acetyl)-2,5-dimethyl-1H-pyrrol-1-yl)benzoate
VU0357121: 4-butoxy-N-(2,4-difluorophenyl)benzamide
VU0366248: N-(3-chloro-2-fluorophenyl)-3-cyano-5-fluorobenzamide
VU0400100: 2-[2-chloro-N-methylsulfonyl-5-(trifluoromethyl)anilino]-N-(cyclopropylmethyl)acetamide
VU0409551: 5-[(4-fluorophenyl)carbonyl]-2-(phenoxymethyl)-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridine
VU0422288: N-(3-chloro-4-((5-chloropyridin-2-yl)oxy)phenyl)picolinamide
VU29: N-(1,3-diphenyl-1H-pyrazolo-5-yl)-4-nitrobenzamide

Authorship Contributions

Wrote or contributed to the writing of the manuscript: Gregory, Conn.

Footnotes

>Karen J. Gregory is a recipient of a National Health and Medical Research Council of Australia (NHMRC) Overseas Biomedical Postdoctoral Training Fellowship; work in her laboratory is supported by a NHMRC project grant [1084775]. Research on metabotropic glutamate receptors in the Conn laboratory is supported by the National Institutes of Health National Institute of Mental Health [Grant R01-MH062646-13], National Institute of Neurological Diseases and Stroke [Grant R01-NS031373-16A2], and National Institute of Drug Abuse [Grant R01-DA023947].

dx.doi.org/10.1124/mol.114.097220.

Inline graphic This article has supplemental material available at molpharm.aspetjournals.org.

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PERMALINK

Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation

Karen J Gregory

P Jeffrey Conn

Abstract

Introduction

Therapeutic Targeting of mGlus with Allosteric Modulators

TABLE 1.

TABLE 2.

TABLE 3.

Complexities of mGlu Receptor Allosteric Modulator Pharmacology

Stimulus-Bias.

Fig. 1.

Biased Modulation.

Probe Dependence.

Protein-Protein Interactions.

Molecular Switches.

Structural Basis of Allosteric Modulation

The Common mGlu Allosteric Site

Fig. 2.

Delineating Affinity versus Cooperativity Determinants

TABLE 4.

Fig. 3.

Fig. 4.

Additional mGlu Allosteric Sites

Concluding Remarks

Supplementary Material

Abbreviations

Authorship Contributions

Footnotes

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation

Karen J Gregory

P Jeffrey Conn

Abstract

Introduction

Therapeutic Targeting of mGlus with Allosteric Modulators

TABLE 1.

TABLE 2.

TABLE 3.

Complexities of mGlu Receptor Allosteric Modulator Pharmacology

Stimulus-Bias.

Fig. 1.

Biased Modulation.

Probe Dependence.

Protein-Protein Interactions.

Molecular Switches.

Structural Basis of Allosteric Modulation

The Common mGlu Allosteric Site

Fig. 2.

Delineating Affinity versus Cooperativity Determinants

TABLE 4.

Fig. 3.

Fig. 4.

Additional mGlu Allosteric Sites

Concluding Remarks

Supplementary Material

Abbreviations

Authorship Contributions

Footnotes

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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