Recent advances in drug discovery of GPCR allosteric ... advances in drug discovery of GPCR allosteric ... symptoms or offer a potential disease-modifying treat-ment for neurodegenerative disorders such as Parkinson

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<ul><li><p>Available online at</p><p>ScienceDirect</p><p>Recent advances in drug discov</p>ery of GPCR allostericmodulators for neurodegenerative disordersRobert Lutjens1 and Jean-Philippe Rocher2<p>The activation or the inhibition of G-protein coupled receptors</p><p>(GPCRs) implicated in the pathophysiology of</p><p>neurodegenerative disorders is considered as a relevant</p><p>approach for the treatment of these diseases. The modulation</p><p>of the relevant GPCRs targets by positive or by negative</p><p>allosteric modulators appears to be promising, the major</p><p>challenge remaining the discovery of these molecules. In this</p><p>review, we highlight the recent development in this field and the</p><p>therapeutic potential of selected GPCRs allosteric modulators.</p><p>Addresses1 Addex Therapeutics, Geneva, Switzerland2 Institut de Recherche Pierre Fabre, CNS Innovation Unit, Toulouse,</p><p>France</p><p>Corresponding author: Rocher, Jean-Philippe</p><p>(</p><p>Current Opinion in Pharmacology 2017, 32:9195</p><p>This review comes from a themed issue on Neurosciences</p><p>Edited by David Chatenet and Terence E. Hebert</p><p>For a complete overview see the Issue and the Editorial</p><p>Available online 27th January 2017</p><p></p><p>1471-4892/# 2017 Elsevier Ltd. All rights reserved.</p><p>IntroductionG-protein coupled receptors (GPCRs) are the largestfamily of transmembrane proteins and numerous allo-steric modulators of this receptor class have been dis-covered [1,2]. Allosteric modulators of GPCR receptorsoffers an opportunity to develop small molecular weightnon peptidic molecules with favorable pharmaceuticalproperties. They can be administered orally and canreadily cross the blood brain barrier. Positive AllostericModulators (PAM) and Negative Allosteric Modulators(NAM) do not activate or inhibit the receptor such asthe ligand does. As such they preserve natural physio-logical rhythms, translating potentially into fewer sideeffects and better efficacy. Because they bind to a sitewhich is topographically distinct from the active siteand with a higher sequence diversity, they can offer anexquisite receptor subtype selectivity. Furthermore,allosterism opens the possibility to control the potency,the efficacy and the functional activity of the drugresponse [3,4].</p><p></p><p>The increased selectivity of the allosteric approach ingroup C GPCRS (among others) has allowed to betterdefine specific neurocircuitries both in physiological andpathological conditions. Among these are a series ofneurodegenerative diseases where the role of one orseveral GPCRs has been lost or perturbed, and allostericmodulators may represent new therapeutic agents able toreinstate (albeit partially) the function [5,6].</p><p>This review is in particular focusing on AM to addresssymptoms or offer a potential disease-modifying treat-ment for neurodegenerative disorders such as Parkinsondisease (mGlu4; mGlu5; adenosine receptors); cerebellarataxia (mGlu1) and Alzheimers disease (mGlu2; mGlu5;M1). Parkinsons disease (PD) is a chronic neurodegen-erative disorder characterized by motor symptoms such asbradykinesia, tremor and rigidity, caused by the progres-sive death of dopamine-producing neurons in the sub-stantia nigra. Current available treatments are aimed atreplacing dopamine using L-dopa or dopamine receptoragonists. But while initially effective in relieving symp-toms, these dopamine replacement strategies wear offand progressively give rise to undesired side-effects suchas dyskinesia [7]. Alzheimers disease (AD) is a progres-sive neurodegenerative disorder leading to loss of mem-ory, cognitive decline, changes in personality andbehavior. Pathological features of the disease includetwo types of hallmarks, beta amyloid plaques and neuro-fibrillary tangles opening an intense focus of research fornovel therapeutic approaches [8].</p><p>Purinergic receptorWe will focus on GPCRs Purine receptors P1 whichrecognizes adenosine and on P2Y receptors which ligandsare nucleotides (ATP and UTP). These receptors aremodulating many pathophysiological functions and theyare involved in neurodegenerative diseases [9,10,11].</p><p>The A2A adenosine receptors are highly expressed in basalganglia neurons and they play a key role in modulatingdopamine signaling. However, as of today, most A2Aantagonists 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 reachedclinical stage, they may prove a better perspective [1214].</p><p>P2Y1 receptors are distributed in the brain and they are aputative target for AD. An allosteric pocket has beenidentified by the recent X-ray co-crystallisation of P2Y1Receptor with a molecule identified as an antagonist [15].</p><p>Current Opinion in Pharmacology 2017, 32:9195</p><p>;</p></li><li><p>92 Neurosciences</p><p>This work may help in the discovery of brain penetrantdrug like Negative Allosteric Modulators.</p><p>Muscarinic acetylcholine receptors (mAchRs)There are many evidences of mAchRs involvement incognitive, memory and motor functions leading to theresearch 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, Alzheimers disease andParkinsons disease [1618]. This was demonstrated in aphase III schizophrenia clinical trial with the M1/M4agonist xanomeline which has shown improvement inpositive, negative symptoms and cognitive functions ben-efits. However, xanomeline has shown gastrointestinalside effects and therefore, a PAM could be a potentiallysafer alternative. Recently, Merck, Vanderbilt, Takedaand Pfizer have identified M1 PAMs active in rodentmodels but gastrointestinal, cardiovascular and convulsionfindings have been reported with M1 PAM compoundsand the safety margin of this class should be well estab-lished [19,20,21]; the termination of the phase IIa/IIbclinical trial conducted with the Merck M1 PAM MK-7622was recently announced. Selective M4 PAM have beendescribed: LY2033298, VU0152100, VU0152099 andVU0467485 have been evaluated in preclinical modelsof schizophrenia [22]; the recent crystallization of the M1and M4 receptors is providing structural basis in themechanism of action of PAMs [23] and the potential inAD of this new class remains to be evaluated.</p><p>Metabotropic glutamate receptorsThe family of metabotropic glutamate (mGlu) receptors,discovered nearly 30 years ago, has been extensivelyinvestigated as drug discovery targets by many academicand industrial groups. mGlu receptors are class C GPCRswith a large extracellular domain binding glutamate with8 subtypes subdivided in 3 groups based on signal trans-duction, sequence homology and pharmacology. Giventhe high conservation between subtypes of the glutamatebinding site, a traditional orthosteric approach to identifyselective compounds has proven extremely difficult. In-stead, with the advent of new dynamic screening meth-ods, identification of allosteric modulators with highpotency and selectivity has yielded valuable pharmaco-logical tools to interrogate the function of the differentmGlu receptor subtypes, and validate potential indica-tions for drug discovery approaches [3]. Today, programsaddressing mGlu2, mGlu4 and mGlu5 have reachedclinical testing stage in man, while other programs addres-sing the other subtypes are on good way to validate theallosteric modulator approach for new indications.</p><p>In the following paragraphs, we summarize achievementsobtained in validating neurodegenerative disorder indica-tions in preclinical and clinical studies involving allostericmodulators of mGlu subtypes [24,25,26].</p><p>Current Opinion in Pharmacology 2017, 32:9195</p><p>Group 1: mGlu1/mGlu5In PD, antagonism of mGluR1 is not a good strategy forthe treatment of dyskinesia [27]. In addition, potentialside effects including cognitive and locomotor impair-ments of mGlu1 receptor blockade have been described[28]. Identification of SNPs in the mGlu1 receptor genehas led to an active research for mGlu1 PAMs anddiscovery of new molecules with favorable developabilityprofile [29]. Because of mGlu1s role in mediating Pur-kinje fiber currents in the cerebellum, mGlu1 PAMscould be useful for the treatment of some subtypes ofcerebella ataxia [30].</p><p>Large efforts were put in the discovery of mGlu5 NAMcompounds, thanks to an early validation of the mecha-nism obtained using prototypical compounds such asMPEP and MTEP. Numerous preclinical studies usingthese compounds have helped validate indications suchas AD and PD [31,32]. However, most compelling resultshave been obtained in several clinical phase 2 studies totreat PD-LID in Parkinsons disease (PD) patients. Clin-ical efficacy in reducing LID has been demonstrated withAFQ056/mavoglurant [33] and ADX48621/dipraglurant[34]. While these results validate the approach to treatsymptoms of PD, recently published reports are suggest-ing a potential disease-modifying effect of mGlu5 NAMsin AD. Pharmacological blockade of mGlu5 receptorsprotects neurons from induced excitotoxic cell deathin vitro and in vivo [35]. Accordingly, genetic removalof mGlu5 in AD model APPswe/PS1DE9 transgenic miceis able to rescue their memory deficits and to reduce Abplaque number and oligomer formation. Interestingly,using a pharmacological rather than a genetic approach,these findings were replicated when APPswe/PS1DE9transgenic mice received a chronic treatment with CTEP,an mGlu5 NAM analog to clinical compound RO-7090/basimglurant [36].</p><p>Positive allosteric modulation of mGlu5 receptors on theother side of the spectra has recently shown potential for aneuroprotective effect in in vitro and in vivo models ofHuntingtons 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 earlystage in the development of AD. However, an mGlu5PAM approach may be hampered by severe side effects,as seizures and neurotoxicity [39] have been reportedwith certain compounds in preclinical studies. Thesedeleterious side effects seem to be linked potentiallyto the level of allosteric agonism of the compounds usedin those studies [40].</p><p>Group 2: mGlu2/mGlu3Inhibition of group 2 mGlu receptors has long beenknown to have a pro-cognitive effect, as demonstratedby early studies using mGlu2/3 orthosteric antagonists</p><p></p></li><li><p>GPCR allosteric modulators for neurodegenerative disorders Lutjens and Rocher 93</p><p>[41]. Chronic treatment with BCI-838 was associated withreversal of transgene-related amnestic behaviour, reduc-tion in anxiety, reduction in levels of brain Ab monomersand oligomers, and stimulation of hippocampal neurogen-esis [42]. RO4432717, an mGlu2/3 NAM showed benefitin 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 toaddress cognitive impairment [43]. Taken together, thesedata are suggesting that mGlu2 activation while neuronsare being exposed to a toxic insult may have a deleteriouseffect on survival, while conversely mGlu2 selectiveinhibition may be beneficial and protect neurons [44,45].</p><p>There are currently only a few examples of selectivemGlu3 PAM molecules described; however, DomainTherapeutics has recently disclosed a series of mGlu3PAMs which have been further characterized in neuro-protection models [46]. mGlu3 activation remains so faran interesting target, as numerous reports using group2 agonists have linked their neuroprotective effect tomGlu3 [44,45,47,48], largely through stimulation of pro-duction of neurotrophic factor such as TGF-b andGDNF. Selective mGlu3 PAM compounds representtherefore a novel approach to promote neuroprotection,and hence potentially disease-modifying agents for thetreatment of neurodegenerative disorders.</p><p>Group 3: mGlu4/mGlu6/mGlu7/mGlu8Within group 3 receptors, mGlu4 has received mostefforts since PHCCC, the first mGlu4 PAM, was reportedand shown to relieve motor symptoms in an animal PDmodel [49]. Since then, several other mGlu4 PAM com-pounds, with increased drug-like properties have demon-strated the potential of the approach for becoming asymptomatic treatment for PD in particular VU0400195(ML182), ADX88178 and Lu AF21934 [5052]. Itappears that mGlu4 PAMs may be used in a dopa-mine-sparing approach, as they potentiate low doses ofL-dopa to generate a full effect on relieving motor symp-toms of PD without increasing LID, possibly extendingthe time L-dopa could be administered without apparitionof 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 neuroprotectiveeffect of mGlu4 PAMs in rodent models of PD [49].Interestingly, PXT002331 is the first mGlu4 PAM tosuccessfully complete phase 1 studies, and will be testedin PD patients in a phase 2 study planned to start in 2017(</p><p>In group 3, mGlu7 receptors may also represent a validtarget for PD, as preclinical studies using AMN082, acompound targeting mGlu7 receptor, in PD models have</p><p></p><p>found antiparkinsonian effects [53]. The pharmacology ofthis compound and the rapid AMN082-induced internal-ization of mGlu7 receptors make it unclear whether theobserved effects are linked to direct activation of thereceptor, or to the functional antagonism resulting fromthe internalization of receptor [54]. There is a clear needfor potent and selective PAM and NAM compounds tointerrogate the function of the receptor and its involve-ment in neurodegenerative disorders.</p><p>ConclusionsValidation of potential of AMs for treatment of neurode-generative disorders has relied on availability of AMs.There is still a need to discover &amp; develop potentcompounds that can be used in animal models to proveor disprove their use as potential treatment. Needed arefor example mGlu3 &amp; mGlu8 selective PAMs, mGlu7selective PAMs or NAMs. AM of mGlu receptors havedemonstrated symptomatic treatment potential. Preclini-cal study in mouse models of AD have shown potentialdisease-modifying effect, in particular mGlu5 NAMs.This needs to be tested in man now. There is an activearea of research regarding the understanding of the regu-latory mechanism of secretase by GPCRs. This may leadto the development of allosteric modulators as alternativetherapeutic strategy for AD [55].</p><p>Besides the target discussed in this...</p></li></ul>