title: Design and synthesis of novel N-sulfonyl-2-indoles that behave as 5-HT6receptor ligands with significant selectivity for D3over D2receptors.
abstract: All clinically-used antipsychotics display similar affinity for both D2(D2R) and D3(D3R) receptors, and they likewise act as 5-HT2Areceptor antagonists. They provide therapeutic benefit for positive symptoms, but no marked or consistent improvement in neurocognitive, social cognitive or negative symptoms. Since blockade of D3and 5-HT6(5-HT6R) receptors enhances neurocognition and social cognition, and potentially improves negative symptoms, a promising approach for improved treatment for schizophrenia would be to develop drugs that preferentially act at D3R versus D2R and likewise recognize 5-HT6R. Starting from the high affinity 5-HT6R ligands I and II, we identified compounds 11a and 14b that behave as 5-HT6R ligands with significant selectivity for D3R over D2R.
authors.affiliation: Université de Montréal, Department of Chemistry, PO Box 6128, Station, Centre-ville, Montréal, Que. H3C 3J7, Canada.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Saavedra
authors.affiliation: Université de Montréal, Department of Chemistry, PO Box 6128, Station, Centre-ville, Montréal, Que. H3C 3J7, Canada.
authors.forename: Delphine
authors.initials: D
authors.lastname: Karila
authors.affiliation: Université de Montréal, Department of Chemistry, PO Box 6128, Station, Centre-ville, Montréal, Que. H3C 3J7, Canada.
authors.forename: Dominique
authors.initials: D
authors.lastname: Brossard
authors.affiliation: Chemistry Pole of Expertise, Institut de Recherches Servier, 3 rue de la République, 92150 Suresnes, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Rojas
authors.affiliation: Centre for Therapeutic Innovation in Neuropsychiatry, Institut de Recherches Servier, 125 chemin de ronde, 78290 Croissy sur Seine, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Dupuis
authors.affiliation: Pole of Expertise Biotechnology-Chemistry-Biology, Institut de Recherches Servier, 125 chemin de ronde, 78290 Croissy sur Seine, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Gohier
authors.affiliation: Centre for Therapeutic Innovation in Neuropsychiatry, Institut de Recherches Servier, 125 chemin de ronde, 78290 Croissy sur Seine, France.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Mannoury la Cour
authors.affiliation: Centre for Therapeutic Innovation in Neuropsychiatry, Institut de Recherches Servier, 125 chemin de ronde, 78290 Croissy sur Seine, France.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.affiliation: Chemistry Pole of Expertise, Institut de Recherches Servier, 3 rue de la République, 92150 Suresnes, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Ortuno
authors.affiliation: Université de Montréal, Department of Chemistry, PO Box 6128, Station, Centre-ville, Montréal, Que. H3C 3J7, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hanessian
mesh_terms: D014150:Antipsychotic Agents / Q000737:chemistry* / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D011083:Polycyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D007211:Indoles; D011083:Polycyclic Compounds; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor; C079040:benzocyclobutene
keywords: Antipsychotic; Benzocyclobutane; CNS receptors; Indole; Schizophrenia