In Vitro and In Vivo Identification of Novel Positive Allosteric Modulators of the Human Dopamine D2 and D3 Receptor

Wood, Martyn; Ateş, Atila; André, Véronique; Michel, Anne; Barnaby, Robert J.; Gillard, Michel

doi:10.1124/mol.115.100172

Cited by 24 publications

(43 citation statements)

References 29 publications

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“…The antidepressant bupropion is racemic as is its major metabolite hydroxybupropion; however, the (2S, 3S)-hydroxy isomer is significantly more potent than the (2S, 3R)- hydroxy isomer (Damaj et al, 2004). In a recent report investigating novel allosteric modulators of dopamine receptors, which are of interest for the treatment of Parkinson's disease, it was found that the (R)-isomer acted as a positive allosteric modulator, whereas the (S)-isomer had negative allosteric modulator properties (Wood et al, 2016). Examples of enantiomers having synergistic properties have also been reported, including enantiomeric iminosugars (Jenkinson et al, 2011) and methadone (Silverman et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

et al. 2017

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The isoprenoid donor for protein geranylgeranylation reactions, geranylgeranyl diphosphate (GGDP), is the product of the enzyme GGDP synthase (GGDPS) that condenses farnesyl diphosphate (FDP) and isopentenyl pyrophosphate. GGDPS inhibition is of interest from a therapeutic perspective for multiple myeloma because we have shown that targeting Rab GTPase geranylgeranylation impairs monoclonal protein trafficking, leading to endoplasmic reticulum stress and apoptosis. We reported a series of triazole bisphosphonate GGDPS inhibitors, of which the most potent was a 3:1 mixture of homogeranyl (HG) and homoneryl (HN) isomers. Here we determined the activity of the individual olefin isomers. Enzymatic and cellular assays revealed that although HN is approximately threefold more potent than HG, HN is not more potent than the original mixture. Studies in which cells were treated with varying concentrations of each isomer alone and in different combinations revealed that the two isomers potentiate the induced-inhibition of protein geranylgeranylation when used in a 3:1 HG:HN combination. A synergistic interaction was observed between the two isomers in the GGDPS enzyme assay. These results suggested that the two isomers bind simultaneously to the enzyme but within different domains. Computational modeling studies revealed that HN is preferred at the FDP site, that HG is preferred at the GGDP site, and that both isomers may bind to the enzyme simultaneously. These studies are the first to report a set of olefin isomers that synergistically inhibit GGDPS, thus establishing a new paradigm for the future development of GGDPS inhibitors.

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Section: Discussionmentioning

confidence: 99%

Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

et al. 2017

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“…Finally, it is worth noting that the indole-2-carboaxamide chemical structure of SB269652 is very similar to a recently identified positive allosteric modulator for D 2 and D 3 receptors, suggesting that understanding the binding mechanism of SB269652 to these receptors could lead to the development of both D 2 and D 3 receptor-specific positive and negative allosteric compounds (Wood et al, 2016).…”

Section: Sb269652 As the Leading Compound That Led To The Developmentmentioning

confidence: 68%

The First Negative Allosteric Modulator for Dopamine D₂and D₃Receptors, SB269652 May Lead to a New Generation of Antipsychotic Drugs

et al. 2017

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D and D dopamine receptors belong to the largest family of cell surface proteins in eukaryotes, the G protein-coupled receptors (GPCRs). Considering their crucial physiologic functions and their relatively accessible cellular locations, GPCRs represent one of the most important classes of therapeutic targets. Until recently, the only strategy to develop drugs regulating GPCR activity was through the identification of compounds that directly acted on the orthosteric sites for endogenous ligands. However, many efforts have recently been made to identify small molecules that are able to interact with allosteric sites. These sites are less well-conserved, therefore allosteric ligands have greater selectivity on the specific receptor. Strikingly, the use of allosteric modulators can provide specific advantages, such as an increased selectivity for GPCR subunits and the ability to introduce specific beneficial therapeutic effects without disrupting the integrity of complex physiologically regulated networks. In 2010, our group unexpectedly found that -[(1r,4r)-4-[2-(7-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-1H-indole-2-carboxamide (SB269652), a compound supposed to interact with the orthosteric binding site of dopamine receptors, was actually a negative allosteric modulator of D- and D-receptor dimers, thus identifying the first allosteric small molecule acting on these important therapeutic targets. This review addresses the progress in understanding the molecular mechanisms of interaction between the negative modulator SB269652 and D and D dopamine receptor monomers and dimers, and surveys the prospects for developing new dopamine receptor allosteric drugs with SB269652 as the leading compound.

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“…Taken together, these results indicate that the 7-CN-THIQ moiety of SB269,652 binds directly to the orthosteric site, while the indole-2-carboxamide portion determines the binding to the second allosteric site. Interestingly, the indole-2-carboxamide part of SB269,652 has a structure similar to another recently discovered positive allosteric modulator for D 2 and D 3 receptors, suggesting the relevance of this second site for developing new allosteric compounds [ 43 ]. Thus, the SB269,652 molecule can be exploited in two different ways, either as a dualsteric compound as it is or eventually as a block from which new allosteric drugs can be generated based on its indole-2-carboxamide moiety.…”

Section: A New Approach To Target Dopamine Receptor Dimers: Bitopic Lmentioning

confidence: 92%

Dopamine D2 Receptors Dimers: How can we Pharmacologically Target Them?

Carli

Kolachalam

Aringhieri

et al. 2018

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BackgroundDopamine D2 and D3 receptors can form homo- and heterodimers and are important targets in Schizophrenia and Parkinson’s. Recently, many efforts have been made to pharmacologically target these receptor complexes. This review focuses on various strategies to act specifically on dopamine receptor dimers, that are transiently formed.MethodsVarious binding and functional assays were reviewed to study the properties of bivalent ligands, particularly for the dualsteric compound SB269,652. The dimerization of D2 and D3 receptors were analyzed by using single particle tracking microscopy.ResultsThe specific targeting of dopamine D2 and D3 dimers can be achieved with bifunctional ligands, composed of two pharmacophores binding the two orthosteric sites of the dimeric complex. If the target is a homodimer, then the ligand is homobivalent. Instead, if the target is a heterodimer, then the ligand is heterobivalent. However, there is some concern regarding pharmacokinetics and binding properties of such drugs. Recently, a new generation of bitopic compounds with dualsteric properties have been discovered that bind to the orthosteric and the allosteric sites in one monomeric receptor. Regarding dopamine D2 and D3 receptors, a new dualsteric molecule SB269,652 was shown to have selective negative allosteric properties across D2 and D3 homodimers, but it behaves as an orthosteric antagonist on receptor monomer. Targeting dimers is also complicated as they are transiently formed with varying monomer/dimer ratio. Furthermore, this ratio can be altered by administering an agonist or a bifunctional antagonist.ConclusionLast 15 years have witnessed an explosive amount of work aimed at generating bifunctional compounds as a novel strategy to target GPCR homo- and heterodimers, including dopamine receptors. Their clinical use is far from trivial, but, at least, they have been used to validate the existence of receptor dimers in-vitro and in-vivo. The dualsteric compound SB269, 652, with its peculiar pharmacological profile, may offer therapeutic advantages and a better tolerability in comparison with pure antagonists at D2 and D3 receptors and pave the way for a new generation of antipsychotic drugs.

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In Vitro and In Vivo Identification of Novel Positive Allosteric Modulators of the Human Dopamine D2 and D3 Receptor

Cited by 24 publications

References 29 publications

Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

The First Negative Allosteric Modulator for Dopamine D₂and D₃Receptors, SB269652 May Lead to a New Generation of Antipsychotic Drugs

Dopamine D2 Receptors Dimers: How can we Pharmacologically Target Them?

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In Vitro and In Vivo Identification of Novel Positive Allosteric Modulators of the Human Dopamine D2 and D3 Receptor

Cited by 24 publications

References 29 publications

Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

The First Negative Allosteric Modulator for Dopamine D2and D3Receptors, SB269652 May Lead to a New Generation of Antipsychotic Drugs

Dopamine D2 Receptors Dimers: How can we Pharmacologically Target Them?

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The First Negative Allosteric Modulator for Dopamine D₂and D₃Receptors, SB269652 May Lead to a New Generation of Antipsychotic Drugs