Design and synthesis of novel N-sulfonyl-2-indoles that behave as 5-HT6 receptor ligands with significant selectivity for D3 over D2 receptors.
作者： Oscar M. Saavedra , Delphine Karila , Dominique Brossard , Anne Rojas , Delphine Dupuis
DOI: 10.1016/J.BMC.2016.10.010
关键词: 5-HT6 receptor 、 Receptor 、 Chemistry 、 Pharmacology 、 Neurocognitive 、 Blockade 、 Selectivity 、 Dopamine receptor D2 、 Schizophrenia 、 Sulfonyl
摘要: All clinically-used antipsychotics display similar affinity for both D2 (D2R) and D3 (D3R) receptors, they likewise act as 5-HT2A receptor antagonists. They provide therapeutic benefit positive symptoms, but no marked or consistent improvement in neurocognitive, social cognitive negative symptoms. Since blockade of 5-HT6 (5-HT6R) receptors enhances neurocognition cognition, potentially improves a promising approach improved treatment schizophrenia would be to develop drugs that preferentially at D3R versus D2R recognize 5-HT6R. Starting from the high 5-HT6R ligands I II, we identified compounds 11a 14b behave with significant selectivity over D2R.
sci-hub.se 参考文章(37)
Robert Luedtke, Claudia Rangel-Barajas, Mahinder Malik, David Reichert, R. Mach, Bitropic D3 Dopamine Receptor Selective Compounds as Potential Antipsychotics. Current Pharmaceutical Design. ,vol. 21, pp. 3700- 3724 ,(2015) , 10.2174/1381612821666150724100830
Mark J. Millan, Benjamin Di Cara, Anne Dekeyne, Fany Panayi, Lotte De Groote, Dorothée Sicard, Laetitia Cistarelli, Rodolphe Billiras, Alain Gobert, Selective blockade of dopamine D3 versus D2 receptors enhances frontocortical cholinergic transmission and social memory in rats: a parallel neurochemical and behavioural analysis Journal of Neurochemistry. ,vol. 100, pp. 1047- 1061 ,(2007) , 10.1111/J.1471-4159.2006.04262.X
Shitij Kapur, David Mamo, Half a century of antipsychotics and still a central role for dopamine D2 receptors Progress in Neuro-Psychopharmacology and Biological Psychiatry. ,vol. 27, pp. 1081- 1090 ,(2003) , 10.1016/J.PNPBP.2003.09.004
Amy Hauck Newman, Peter Grundt, George Cyriac, Jeffrey R Deschamps, Michelle Taylor, Rakesh Kumar, David Ho, Robert R Luedtke, None, N-(4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with functionalized linking chains as high affinity and enantioselective D3 receptor antagonists. Journal of Medicinal Chemistry. ,vol. 52, pp. 2559- 2570 ,(2009) , 10.1021/JM900095Y
Thierry Dubuffet, Adrian Newman-Tancredi, Didier Cussac, Valerie Audinot, Annie Loutz, Mark J Millan, Gilbert Lavielle, None, Novel benzopyrano[3,4-c]pyrrole derivatives as potent and selective dopamine D3 receptor antagonists Bioorganic & Medicinal Chemistry Letters. ,vol. 9, pp. 2059- 2064 ,(1999) , 10.1016/S0960-894X(99)00312-1
Giancarlo Trani, Stuart M. Baddeley, Michael A. Briggs, Tsu T. Chuang, Nigel J. Deeks, Christopher N. Johnson, Abir A. Khazragi, Tania L. Mead, Andrew D. Medhurst, Peter H. Milner, Leann P. Quinn, Alison M. Ray, Dean A. Rivers, Tania O. Stean, Geoffrey Stemp, Brenda K. Trail, David R. Witty, Tricyclic azepine derivatives as selective brain penetrant 5-HT6 receptor antagonists Bioorganic & Medicinal Chemistry Letters. ,vol. 18, pp. 5698- 5700 ,(2008) , 10.1016/J.BMCL.2008.08.010
Mark J. Millan, Clotilde Mannoury la Cour, Francesca Novi, Roberto Maggio, Valérie Audinot, Adrian Newman-Tancredi, Didier Cussac, Valérie Pasteau, Jean-A. Boutin, Thierry Dubuffet, Gilbert Lavielle, S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], A Preferential Dopamine D3 versus D2 Receptor Antagonist and Potential Antipsychotic Agent: I. Receptor-Binding Profile and Functional Actions at G-Protein-Coupled Receptors Journal of Pharmacology and Experimental Therapeutics. ,vol. 324, pp. 587- 599 ,(2008) , 10.1124/JPET.107.126706
M. Nietert, H. Stark, G. Schneider, A. Böcker, B. C. Sasse, GPCR Targeted Library Design: Novel Dopamine D3 Receptor Ligands ChemMedChem. ,vol. 2, pp. 1000- 1005 ,(2007) , 10.1002/CMDC.200700067
Stefan Leucht, Andrea Cipriani, Loukia Spineli, Dimitris Mavridis, Deniz Örey, Franziska Richter, Myrto Samara, Corrado Barbui, Rolf R Engel, John R Geddes, Werner Kissling, Marko Paul Stapf, Bettina Lässig, Georgia Salanti, John M Davis, Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis The Lancet. ,vol. 382, pp. 951- 962 ,(2013) , 10.1016/S0140-6736(13)60733-3
Jim J. Hagan, Emiliangelo A. Ratti, Vincenzo Garzya, Ian T. Forbes, Andrew D. Gribble, Mike S. Hadley, Andrew P. Lightfoot, Andrew H. Payne, Alexander B. Smith, Sara E. Douglas, David G. Cooper, Ian G. Stansfield, Malcom Meeson, Emma E. Dodds, Declan N.C. Jones, Martyn Wood, Charlie Reavill, Carol A. Scorer, Angela Worby, Graham Riley, Peter Eddershaw, Chris Ioannou, Daniele Donati, Studies towards the identification of a new generation of atypical antipsychotic agents. Bioorganic & Medicinal Chemistry Letters. ,vol. 17, pp. 400- 405 ,(2007) , 10.1016/J.BMCL.2006.10.036