Synthesis and SAR of highly potent dual 5-HT1A and 5-HT1B antagonists as potential antidepressant drugs
Novel 5-HT(1) autoreceptor ligands based on the N-4-aryl-piperazinyl-N'-ethyl-5,6,7,8-tetrahydropyrido[4', 3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one core are described. Aiming at antidepressants with a novel mode of action our objective was to identify potent antagonists showing balance...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2005-12, Vol.15 (24), p.5567-5573 |
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| creator | KLING, Andreas LANGE, Udo E. W UNGER, Liliane WICKE, Karsten SCHELLHAAS, Kurt STEINER, Gerd MACK, Helmut BAKKER, Margot H. M DRESCHER, Karla U HORNBERGER, Wilfried HUTCHINS, Charles W MÖLLER, Achim MÜLLER, Reinhold SCHMIDT, Martin |
| description | Novel 5-HT(1) autoreceptor ligands based on the N-4-aryl-piperazinyl-N'-ethyl-5,6,7,8-tetrahydropyrido[4', 3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one core are described. Aiming at antidepressants with a novel mode of action our objective was to identify potent antagonists showing balanced affinities and high selectivity for the 5-HT(1A) and 5-HT(1B) receptors. Strategies for the development of dual 5-HT(1A) and 5-HT(1B) antagonists based on 1 and 2 as leads and the corresponding results are discussed. Isoquinoline analogue 33 displayed high affinity and an antagonistic mode of action for the 5-HT(1A) and the 5-HT(1B) receptors and was characterized further with respect to selectivity, electrically stimulated [(3)H]5-HT release and in vivo efficacy. |
| doi_str_mv | 10.1016/j.bmcl.2005.04.077 |
| format | Article |
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W ; UNGER, Liliane ; WICKE, Karsten ; SCHELLHAAS, Kurt ; STEINER, Gerd ; MACK, Helmut ; BAKKER, Margot H. M ; DRESCHER, Karla U ; HORNBERGER, Wilfried ; HUTCHINS, Charles W ; MÖLLER, Achim ; MÜLLER, Reinhold ; SCHMIDT, Martin</creator><creatorcontrib>KLING, Andreas ; LANGE, Udo E. W ; UNGER, Liliane ; WICKE, Karsten ; SCHELLHAAS, Kurt ; STEINER, Gerd ; MACK, Helmut ; BAKKER, Margot H. M ; DRESCHER, Karla U ; HORNBERGER, Wilfried ; HUTCHINS, Charles W ; MÖLLER, Achim ; MÜLLER, Reinhold ; SCHMIDT, Martin</creatorcontrib><description>Novel 5-HT(1) autoreceptor ligands based on the N-4-aryl-piperazinyl-N'-ethyl-5,6,7,8-tetrahydropyrido[4', 3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one core are described. Aiming at antidepressants with a novel mode of action our objective was to identify potent antagonists showing balanced affinities and high selectivity for the 5-HT(1A) and 5-HT(1B) receptors. Strategies for the development of dual 5-HT(1A) and 5-HT(1B) antagonists based on 1 and 2 as leads and the corresponding results are discussed. Isoquinoline analogue 33 displayed high affinity and an antagonistic mode of action for the 5-HT(1A) and the 5-HT(1B) receptors and was characterized further with respect to selectivity, electrically stimulated [(3)H]5-HT release and in vivo efficacy.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2005.04.077</identifier><identifier>PMID: 16219465</identifier><language>eng</language><publisher>Oxford: Elsevier</publisher><subject>Antidepressive Agents - chemical synthesis ; Antidepressive Agents - chemistry ; Antidepressive Agents - pharmacology ; Biological and medical sciences ; Humans ; Indoles - chemistry ; Indoles - pharmacology ; Kinetics ; Medical sciences ; Models, Molecular ; Neuropharmacology ; Neurotransmitters. Neurotransmission. 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W</creatorcontrib><creatorcontrib>UNGER, Liliane</creatorcontrib><creatorcontrib>WICKE, Karsten</creatorcontrib><creatorcontrib>SCHELLHAAS, Kurt</creatorcontrib><creatorcontrib>STEINER, Gerd</creatorcontrib><creatorcontrib>MACK, Helmut</creatorcontrib><creatorcontrib>BAKKER, Margot H. M</creatorcontrib><creatorcontrib>DRESCHER, Karla U</creatorcontrib><creatorcontrib>HORNBERGER, Wilfried</creatorcontrib><creatorcontrib>HUTCHINS, Charles W</creatorcontrib><creatorcontrib>MÖLLER, Achim</creatorcontrib><creatorcontrib>MÜLLER, Reinhold</creatorcontrib><creatorcontrib>SCHMIDT, Martin</creatorcontrib><title>Synthesis and SAR of highly potent dual 5-HT1A and 5-HT1B antagonists as potential antidepressant drugs</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Novel 5-HT(1) autoreceptor ligands based on the N-4-aryl-piperazinyl-N'-ethyl-5,6,7,8-tetrahydropyrido[4', 3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one core are described. Aiming at antidepressants with a novel mode of action our objective was to identify potent antagonists showing balanced affinities and high selectivity for the 5-HT(1A) and 5-HT(1B) receptors. Strategies for the development of dual 5-HT(1A) and 5-HT(1B) antagonists based on 1 and 2 as leads and the corresponding results are discussed. Isoquinoline analogue 33 displayed high affinity and an antagonistic mode of action for the 5-HT(1A) and the 5-HT(1B) receptors and was characterized further with respect to selectivity, electrically stimulated [(3)H]5-HT release and in vivo efficacy.</description><subject>Antidepressive Agents - chemical synthesis</subject><subject>Antidepressive Agents - chemistry</subject><subject>Antidepressive Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Humans</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacology</subject><subject>Kinetics</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperazines - chemistry</subject><subject>Piperazines - pharmacology</subject><subject>Serotonin 5-HT1 Receptor Antagonists</subject><subject>Serotoninergic system</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkEFLw0AQhRdRtFb_gAfJRW-JM5tNdvdYi1qhINgK3pZtdtOmpEnNJIf-e1Mb8DQP5nvv8DF2hxAhYPq0jVa7rIw4QBKBiEDKMzZCkYowFpCcsxHoFEKlxfcVuybaAqAAIS7ZFaYctUiTEVsvDlW78VRQYCsXLCafQZ0Hm2K9KQ_Bvm591Qaus2WQhLMlTv6gv_jcx9au66qgtu_SABc92j8K5_eNJ7LHetOt6YZd5LYkfzvcMft6fVlOZ-H84-19OpmHGU-xDbVTnvMchHYopIAcnLOcI2pErqRSSscitS4Di9prKbXMrU147L2THkU8Zo-n3X1T_3SeWrMrKPNlaStfd2RSJYVCrXuQn8CsqYkan5t9U-xsczAI5qjXbM1RrznqNSBMr7cv3Q_r3Wrn3X9l8NkDDwNgKbNl3tgqK-ifkzyOUWH8C5UMgtU</recordid><startdate>20051215</startdate><enddate>20051215</enddate><creator>KLING, Andreas</creator><creator>LANGE, Udo E. 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| ispartof | Bioorganic & medicinal chemistry letters, 2005-12, Vol.15 (24), p.5567-5573 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Antidepressive Agents - chemical synthesis Antidepressive Agents - chemistry Antidepressive Agents - pharmacology Biological and medical sciences Humans Indoles - chemistry Indoles - pharmacology Kinetics Medical sciences Models, Molecular Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Piperazines - chemistry Piperazines - pharmacology Serotonin 5-HT1 Receptor Antagonists Serotoninergic system Structure-Activity Relationship |
| title | Synthesis and SAR of highly potent dual 5-HT1A and 5-HT1B antagonists as potential antidepressant drugs |
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