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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• 作者：Oscar M. Saavedra^a ; Delphine Karila^a ; Dominique Brossard^a ; Anne Rojas^b ; Delphine Dupuis^c ; Arnaud Gohier^d ; Clotilde Mannoury la Cour^c ; Mark J. Millan^c ; ; Jean-Claude Ortuno^b ; ; Stephen Hanessian^a ;
• 关键词：Benzocyclobutane ; Indole ; CNS receptors ; Schizophrenia ; Antipsychotic
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：25
• 期：1
• 页码：38-52
• 全文大小：2508 K
• 卷排序：25

文摘

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.