title: The First Negative Allosteric Modulator for Dopamine D2and D3Receptors, SB269652 May Lead to a New Generation of Antipsychotic Drugs.
abstract: D2and D3dopamine 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 thatN-[(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 D2and D3dopamine receptor monomers and dimers, and surveys the prospects for developing new dopamine receptor allosteric drugs with SB269652 as the leading compound.
authors.affiliation: 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.).
authors.forename: Mario
authors.initials: M
authors.lastname: Rossi
authors.affiliation: 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.).
authors.forename: Irene
authors.initials: I
authors.lastname: Fasciani
authors.affiliation: 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.).
authors.forename: Francesco
authors.initials: F
authors.lastname: Marampon
authors.affiliation: 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.) roberto.maggio@univaq.it marco.scarselli@med.unipi.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Maggio
authors.affiliation: 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.) roberto.maggio@univaq.it marco.scarselli@med.unipi.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Scarselli
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000495:Allosteric Site / Q000187:drug effects / Q000502:physiology; D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D065127:Dopamine D2 Receptor Antagonists / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology*; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors* / Q000502:physiology*
chemical_list: C553924:1H-indole-2-carboxylic acid (4-(2-(cyano-3,4-dihydro-1H-isoquinolin-2-yl)ethyl)cyclohexyl)amide; D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D007211:Indoles; D007546:Isoquinolines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3