Available online at www.sciencedirect.com

ScienceDirect

Recent advances in drug discov

ery of GPCR allostericmodulators for neurodegenerative disordersRobert Lutjens1 and Jean-Philippe Rocher2

The activation or the inhibition of G-protein coupled receptors

(GPCRs) implicated in the pathophysiology of

neurodegenerative disorders is considered as a relevant

approach for the treatment of these diseases. The modulation

of the relevant GPCRs targets by positive or by negative

allosteric modulators appears to be promising, the major

challenge remaining the discovery of these molecules. In this

review, we highlight the recent development in this field and the

therapeutic potential of selected GPCRs allosteric modulators.

Addresses1 Addex Therapeutics, Geneva, Switzerland2 Institut de Recherche Pierre Fabre, CNS Innovation Unit, Toulouse,

France

Corresponding author: Rocher, Jean-Philippe

(jean.philippe.rocher@pierre-fabre.com)

Current Opinion in Pharmacology 2017, 32:91–95

This review comes from a themed issue on Neurosciences

Edited by David Chatenet and Terence E. Hebert

For a complete overview see the Issue and the Editorial

Available online 27th January 2017

http://dx.doi.org/10.1016/j.coph.2017.01.001

1471-4892/# 2017 Elsevier Ltd. All rights reserved.

IntroductionG-protein coupled receptors (GPCRs) are the largest

family of transmembrane proteins and numerous allo-

steric modulators of this receptor class have been dis-

covered [1,2]. Allosteric modulators of GPCR receptors

offers an opportunity to develop small molecular weight

non peptidic molecules with favorable pharmaceutical

properties. They can be administered orally and can

readily cross the blood brain barrier. Positive Allosteric

Modulators (PAM) and Negative Allosteric Modulators

(NAM) do not activate or inhibit the receptor such as

the ligand does. As such they preserve natural physio-

logical rhythms, translating potentially into fewer side

effects and better efficacy. Because they bind to a site

which is topographically distinct from the active site

and with a higher sequence diversity, they can offer an

exquisite receptor subtype selectivity. Furthermore,

allosterism opens the possibility to control the potency,

the efficacy and the functional activity of the drug

response [3�,4].

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The increased selectivity of the allosteric approach in

group C GPCRS (among others) has allowed to better

define specific neurocircuitries both in physiological and

pathological conditions. Among these are a series of

neurodegenerative diseases where the role of one or

several GPCRs has been lost or perturbed, and allosteric

modulators may represent new therapeutic agents able to

reinstate (albeit partially) the function [5,6].

This review is in particular focusing on AM to address

symptoms or offer a potential disease-modifying treat-

ment for neurodegenerative disorders such as Parkinson

disease (mGlu4; mGlu5; adenosine receptors); cerebellar

ataxia (mGlu1) and Alzheimer’s disease (mGlu2; mGlu5;

M1). Parkinson’s disease (PD) is a chronic neurodegen-

erative disorder characterized by motor symptoms such as

bradykinesia, tremor and rigidity, caused by the progres-

sive death of dopamine-producing neurons in the sub-

stantia nigra. Current available treatments are aimed at

replacing dopamine using L-dopa or dopamine receptor

agonists. But while initially effective in relieving symp-

toms, these dopamine replacement strategies wear off

and progressively give rise to undesired side-effects such

as dyskinesia [7]. Alzheimer’s disease (AD) is a progres-

sive neurodegenerative disorder leading to loss of mem-

ory, cognitive decline, changes in personality and

behavior. Pathological features of the disease include

two types of hallmarks, beta amyloid plaques and neuro-

fibrillary tangles opening an intense focus of research for

novel therapeutic approaches [8].

Purinergic receptorWe will focus on GPCRs Purine receptors P1 which

recognizes adenosine and on P2Y receptors which ligands

are nucleotides (ATP and UTP). These receptors are

modulating many pathophysiological functions and they

are involved in neurodegenerative diseases [9,10��,11].

The A2A adenosine receptors are highly expressed in basal

ganglia neurons and they play a key role in modulating

dopamine signaling. However, as of today, most A2A

antagonists have failed in late stage clinical development,

except istradefylline which is approved in Japan as adjunc-

tive treatment for PD; although no AM have yet reached

clinical stage, they may prove a better perspective [12–14].

P2Y1 receptors are distributed in the brain and they are a

putative target for AD. An allosteric pocket has been

identified by the recent X-ray co-crystallisation of P2Y1

Receptor with a molecule identified as an antagonist [15].

Current Opinion in Pharmacology 2017, 32:91–95

92 Neurosciences

This work may help in the discovery of brain penetrant

drug like Negative Allosteric Modulators.

Muscarinic acetylcholine receptors (mAchRs)There are many evidences of mAchRs involvement in

cognitive, memory and motor functions leading to the

research of pharmacological agents which could selec-

tively increase the impaired cholinergic transmission [5].

M1 and M4 mAchRs subclasses are considered as impor-

tant targets for schizophrenia, Alzheimer’s disease and

Parkinson’s disease [16–18]. This was demonstrated in a

phase III schizophrenia clinical trial with the M1/M4

agonist xanomeline which has shown improvement in

positive, negative symptoms and cognitive functions ben-

efits. However, xanomeline has shown gastrointestinal

side effects and therefore, a PAM could be a potentially

safer alternative. Recently, Merck, Vanderbilt, Takeda

and Pfizer have identified M1 PAMs active in rodent

models but gastrointestinal, cardiovascular and convulsion

findings have been reported with M1 PAM compounds

and the safety margin of this class should be well estab-

lished [19,20,21�]; the termination of the phase IIa/IIb

clinical trial conducted with the Merck M1 PAM MK-7622

was recently announced. Selective M4 PAM have been

described: LY2033298, VU0152100, VU0152099 and

VU0467485 have been evaluated in preclinical models

of schizophrenia [22]; the recent crystallization of the M1

and M4 receptors is providing structural basis in the

mechanism of action of PAMs [23] and the potential in

AD of this new class remains to be evaluated.

Metabotropic glutamate receptorsThe family of metabotropic glutamate (mGlu) receptors,

discovered nearly 30 years ago, has been extensively

investigated as drug discovery targets by many academic

and industrial groups. mGlu receptors are class C GPCRs

with a large extracellular domain binding glutamate with

8 subtypes subdivided in 3 groups based on signal trans-

duction, sequence homology and pharmacology. Given

the high conservation between subtypes of the glutamate

binding site, a traditional orthosteric approach to identify

selective compounds has proven extremely difficult. In-

stead, with the advent of new dynamic screening meth-

ods, identification of allosteric modulators with high

potency and selectivity has yielded valuable pharmaco-

logical tools to interrogate the function of the different

mGlu receptor subtypes, and validate potential indica-

tions for drug discovery approaches [3�]. Today, programs

addressing mGlu2, mGlu4 and mGlu5 have reached

clinical testing stage in man, while other programs addres-

sing the other subtypes are on good way to validate the

allosteric modulator approach for new indications.

In the following paragraphs, we summarize achievements

obtained in validating neurodegenerative disorder indica-

tions in preclinical and clinical studies involving allosteric

modulators of mGlu subtypes [24,25��,26��].

Current Opinion in Pharmacology 2017, 32:91–95

Group 1: mGlu1/mGlu5In PD, antagonism of mGluR1 is not a good strategy for

the treatment of dyskinesia [27]. In addition, potential

side effects including cognitive and locomotor impair-

ments of mGlu1 receptor blockade have been described

[28]. Identification of SNPs in the mGlu1 receptor gene

has led to an active research for mGlu1 PAMs and

discovery of new molecules with favorable developability

profile [29]. Because of mGlu1’s role in mediating Pur-

kinje fiber currents in the cerebellum, mGlu1 PAMs

could be useful for the treatment of some subtypes of

cerebella ataxia [30�].

Large efforts were put in the discovery of mGlu5 NAM

compounds, thanks to an early validation of the mecha-

nism obtained using prototypical compounds such as

MPEP and MTEP. Numerous preclinical studies using

these compounds have helped validate indications such

as AD and PD [31,32]. However, most compelling results

have been obtained in several clinical phase 2 studies to

treat PD-LID in Parkinson’s disease (PD) patients. Clin-

ical efficacy in reducing LID has been demonstrated with

AFQ056/mavoglurant [33] and ADX48621/dipraglurant

[34]. While these results validate the approach to treat

symptoms of PD, recently published reports are suggest-

ing a potential disease-modifying effect of mGlu5 NAMs

in AD. Pharmacological blockade of mGlu5 receptors

protects neurons from induced excitotoxic cell death

in vitro and in vivo [35]. Accordingly, genetic removal

of mGlu5 in AD model APPswe/PS1DE9 transgenic mice

is able to rescue their memory deficits and to reduce Ab

plaque number and oligomer formation. Interestingly,

using a pharmacological rather than a genetic approach,

these findings were replicated when APPswe/PS1DE9

transgenic mice received a chronic treatment with CTEP,

an mGlu5 NAM analog to clinical compound RO-7090/

basimglurant [36��].

Positive allosteric modulation of mGlu5 receptors on the

other side of the spectra has recently shown potential for a

neuroprotective effect in in vitro and in vivo models of

Huntington’s disease [37]. mGlu5 PAMs have demon-

strated pro-cognitive effects in preclinical studies, sug-

gesting a potential pro-cognitive use of such compounds

[38] to treat Mild cognitive impairment (MCI), an early

stage in the development of AD. However, an mGlu5

PAM approach may be hampered by severe side effects,

as seizures and neurotoxicity [39] have been reported

with certain compounds in preclinical studies. These

deleterious side effects seem to be linked potentially

to the level of allosteric agonism of the compounds used

in those studies [40].

Group 2: mGlu2/mGlu3Inhibition of group 2 mGlu receptors has long been

known to have a pro-cognitive effect, as demonstrated

by early studies using mGlu2/3 orthosteric antagonists

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GPCR allosteric modulators for neurodegenerative disorders Lutjens and Rocher 93

[41]. Chronic treatment with BCI-838 was associated with

reversal of transgene-related amnestic behaviour, reduc-

tion in anxiety, reduction in levels of brain Ab monomers

and oligomers, and stimulation of hippocampal neurogen-

esis [42]. RO4432717, an mGlu2/3 NAM showed benefit

in tests of short term memory (delayed match to position),

cognitive flexibility (Morris water maze, reversal proto-

col), impulsivity and compulsivity (5-choice serial reac-

tion time) and spontaneous object recognition in rodents,

providing first evidence of a profile potentially relevant to

address cognitive impairment [43]. Taken together, these

data are suggesting that mGlu2 activation while neurons

are being exposed to a toxic insult may have a deleterious

effect on survival, while conversely mGlu2 selective

inhibition may be beneficial and protect neurons [44,45].

There are currently only a few examples of selective

mGlu3 PAM molecules described; however, Domain

Therapeutics has recently disclosed a series of mGlu3

PAMs which have been further characterized in neuro-

protection models [46]. mGlu3 activation remains so far

an interesting target, as numerous reports using group

2 agonists have linked their neuroprotective effect to

mGlu3 [44,45,47,48], largely through stimulation of pro-

duction of neurotrophic factor such as TGF-b and

GDNF. Selective mGlu3 PAM compounds represent

therefore a novel approach to promote neuroprotection,

and hence potentially disease-modifying agents for the

treatment of neurodegenerative disorders.

Group 3: mGlu4/mGlu6/mGlu7/mGlu8Within group 3 receptors, mGlu4 has received most

efforts since PHCCC, the first mGlu4 PAM, was reported

and shown to relieve motor symptoms in an animal PD

model [49]. Since then, several other mGlu4 PAM com-

pounds, with increased drug-like properties have demon-

strated the potential of the approach for becoming a

symptomatic treatment for PD in particular VU0400195

(ML182), ADX88178 and Lu AF21934 [50–52]. It

appears that mGlu4 PAMs may be used in a dopa-

mine-sparing approach, as they potentiate low doses of

L-dopa to generate a full effect on relieving motor symp-

toms of PD without increasing LID, possibly extending

the time L-dopa could be administered without apparition

of dyskinesia in PD patients. In addition to the symp-

tomatic treatment of PD, a potential for disease modify-

ing effect stems from studies showing a neuroprotective

effect of mGlu4 PAMs in rodent models of PD [49].

Interestingly, PXT002331 is the first mGlu4 PAM to

successfully complete phase 1 studies, and will be tested

in PD patients in a phase 2 study planned to start in 2017

(http://www.biospace.com/News/parkinsons-disease-

prexton-therapeutics-completes/432799).

In group 3, mGlu7 receptors may also represent a valid

target for PD, as preclinical studies using AMN082, a

compound targeting mGlu7 receptor, in PD models have

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found antiparkinsonian effects [53]. The pharmacology of

this compound and the rapid AMN082-induced internal-

ization of mGlu7 receptors make it unclear whether the

observed effects are linked to direct activation of the

receptor, or to the functional antagonism resulting from

the internalization of receptor [54]. There is a clear need

for potent and selective PAM and NAM compounds to

interrogate the function of the receptor and its involve-

ment in neurodegenerative disorders.

ConclusionsValidation of potential of AMs for treatment of neurode-

generative disorders has relied on availability of AMs.

There is still a need to discover & develop potent

compounds that can be used in animal models to prove

or disprove their use as potential treatment. Needed are

for example mGlu3 & mGlu8 selective PAMs, mGlu7

selective PAMs or NAMs. AM of mGlu receptors have

demonstrated symptomatic treatment potential. Preclini-

cal study in mouse models of AD have shown potential

disease-modifying effect, in particular mGlu5 NAMs.

This needs to be tested in man now. There is an active

area of research regarding the understanding of the regu-

latory mechanism of secretase by GPCRs. This may lead

to the development of allosteric modulators as alternative

therapeutic strategy for AD [55�].

Besides the target discussed in this review, there are

promising classes of GPCRS like adhesion GPCRs di-

rectly involved in many aspects of neurodegeneration

which could become the next frontier for allosterism in

the coming years [56].

Conflicts of interestNothing declared.

AcknowledgementWe thank Dr Silvia Gatti for helpul discussions.

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55.�

Zhao J, Deng Y, Jiang Z, Qing H: G protein-coupled receptors(GPCRs) in Alzheimer’s disease: a focus on BACE1 relatedGPCRs. Front Aging Neurosci 2016, 8:58.

This thorough review highlights the interaction between GPCRs andBACE1 with perspectives for AM in the therapeutic approaches of AD.

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Current Opinion in Pharmacology 2017, 32:91–95