Design and synthesis of novel N-sulfonyl-2-indoles that behave as 5-HT6 receptor ligands with significant selectivity for D3 over D2 receptors |
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| Authors: | Oscar M. Saavedra Delphine Karila Dominique Brossard Anne Rojas Delphine Dupuis Arnaud Gohier Clotilde Mannoury la Cour Mark J. Millan Jean-Claude Ortuno Stephen Hanessian |
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| Affiliation: | 1. Université de Montréal, Department of Chemistry, PO Box 6128, Station, Centre-ville, Montréal, Que. H3C 3J7, Canada;2. Chemistry Pole of Expertise, Institut de Recherches Servier, 3 rue de la République, 92150 Suresnes, France;3. Centre for Therapeutic Innovation in Neuropsychiatry, Institut de Recherches Servier, 125 chemin de ronde, 78290 Croissy sur Seine, France;4. Pole of Expertise Biotechnology-Chemistry-Biology, Institut de Recherches Servier, 125 chemin de ronde, 78290 Croissy sur Seine, France |
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| Abstract: | ![]()
All clinically-used antipsychotics display similar affinity for both D2 (D2R) and D3 (D3R) receptors, and they likewise act as 5-HT2A receptor antagonists. They provide therapeutic benefit for positive symptoms, but no marked or consistent improvement in neurocognitive, social cognitive or negative symptoms. Since blockade of D3 and 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. |
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| Keywords: | Benzocyclobutane Indole CNS receptors Schizophrenia Antipsychotic |
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