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Molecular Pharmacology

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Rapid CommunicationMinireview

The First Negative Allosteric Modulator for Dopamine D2 and D3 Receptors, SB269652 May Lead to a New Generation of Antipsychotic Drugs

Mario Rossi, Irene Fasciani, Francesco Marampon, Roberto Maggio and Marco Scarselli
Molecular Pharmacology June 2017, 91 (6) 586-594; DOI: https://doi.org/10.1124/mol.116.107607
Mario Rossi
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland (M.R.); Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy (I.F., F.M., R.M.); Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy (M.S.)
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Irene Fasciani
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland (M.R.); Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy (I.F., F.M., R.M.); Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy (M.S.)
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Francesco Marampon
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland (M.R.); Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy (I.F., F.M., R.M.); Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy (M.S.)
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Roberto Maggio
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland (M.R.); Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy (I.F., F.M., R.M.); Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy (M.S.)
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Marco Scarselli
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland (M.R.); Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy (I.F., F.M., R.M.); Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy (M.S.)
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Abstract

D2 and D3 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 N-[(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 D2- and D3-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 D2 and D3 dopamine receptor monomers and dimers, and surveys the prospects for developing new dopamine receptor allosteric drugs with SB269652 as the leading compound.

Footnotes

    • Received November 30, 2016.
    • Accepted March 2, 2017.
  • This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.

  • https://doi.org/10.1124/mol.116.107607.

  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 91 (6)
Molecular Pharmacology
Vol. 91, Issue 6
1 Jun 2017
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Rapid CommunicationMinireview

Allosteric Modulators as New Generation Antipsychotics

Mario Rossi, Irene Fasciani, Francesco Marampon, Roberto Maggio and Marco Scarselli
Molecular Pharmacology June 1, 2017, 91 (6) 586-594; DOI: https://doi.org/10.1124/mol.116.107607

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Rapid CommunicationMinireview

Allosteric Modulators as New Generation Antipsychotics

Mario Rossi, Irene Fasciani, Francesco Marampon, Roberto Maggio and Marco Scarselli
Molecular Pharmacology June 1, 2017, 91 (6) 586-594; DOI: https://doi.org/10.1124/mol.116.107607
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  • Article
    • Abstract
    • Introduction
    • SB269652 Is an Atypical Allosteric Modulator for D2 and D3 Dopamine Receptors
    • SB269652 Influence on the Radioligand Dissociation Constant Reveals Additional Complexity
    • SB269652 as the Leading Compound That Led to the Development of New Antipsychotic Drugs
    • Dopamine Receptor Dimerization and Allosteric Effect of SB269652
    • Allosteric Drugs as New Antipsychotic Agents
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