Synthesis and structure–activity relationships of novel arylpiperazines as potent antagonists of α1-adrenoceptor
Arylpiperazines 2–11 were synthesized, and their biological profiles at α1-adrenergic receptors (α1-ARs) assessed by binding assays in CHO cells expressing human cloned subtypes and by functional experiments in isolated rat vas deferens (α1A), spleen (α1B), and aorta (α1D). Modifications at the 1,3-...
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| Veröffentlicht in: | European journal of medicinal chemistry 2016-10, Vol.122, p.601-610 |
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| creator | Silva, Renata Oliveira de Oliveira, Andressa Souza Nunes Lemes, Laís Flávia de Camargo Nascente, Luciana Coelho do Nascimento Nogueira, Patrícia Silveira, Edilberto R. Brand, Guilherme D. Vistoli, Giulio Cilia, Antonio Poggesi, Elena Buccioni, Michela Marucci, Gabriella Bolognesi, Maria Laura Romeiro, Luiz Antonio Soares |
| description | Arylpiperazines 2–11 were synthesized, and their biological profiles at α1-adrenergic receptors (α1-ARs) assessed by binding assays in CHO cells expressing human cloned subtypes and by functional experiments in isolated rat vas deferens (α1A), spleen (α1B), and aorta (α1D). Modifications at the 1,3-benzodioxole and phenyl phamacophoric units resulted in the identification of a number of potent compounds (moderately selective with respect to the α1b-AR), in binding experiments. Notably, compound 7 (LDT451) showed a subnanomolar pKi of 9.41 towards α1a-AR. An encouragingly lower α1B-potency was a general trend for all the series of compounds, which showed α1A/D over α1B selectivity in functional assays. If adequately optimized, such peculiar selectivity could have relevance for a potential LUTS/BPH therapeutic application.
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•11 new phenylpiperazines derived from LASSBio 772 has been designed and synthesized.•Affinities for human α1-AR subtypes in radioligand binding assays were assessed.•Antagonist profiles at α1-AR subtypes in functional bioassays were evaluated.•Among the newly synthesized compounds, potent ligands were identified.•SAR-analysis identified new hits for further search for improved α1-AR agents. |
| doi_str_mv | 10.1016/j.ejmech.2016.06.052 |
| format | Article |
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[Display omitted]
•11 new phenylpiperazines derived from LASSBio 772 has been designed and synthesized.•Affinities for human α1-AR subtypes in radioligand binding assays were assessed.•Antagonist profiles at α1-AR subtypes in functional bioassays were evaluated.•Among the newly synthesized compounds, potent ligands were identified.•SAR-analysis identified new hits for further search for improved α1-AR agents.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2016.06.052</identifier><identifier>PMID: 27448917</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Adrenergic alpha-1 Receptor Antagonists - chemical synthesis ; Adrenergic alpha-1 Receptor Antagonists - chemistry ; Adrenergic alpha-1 Receptor Antagonists - metabolism ; Adrenergic alpha-1 Receptor Antagonists - pharmacology ; Adrenergic receptors subtypes ; Animals ; Arylpiperazines ; BPH ; Cell Line, Tumor ; Chemistry Techniques, Synthetic ; CHO Cells ; Cloning, Molecular ; Cricetinae ; Cricetulus ; Drug Design ; Humans ; Male ; Molecular Docking Simulation ; Muscle, Smooth, Vascular - cytology ; Muscle, Smooth, Vascular - drug effects ; Piperazines - chemical synthesis ; Piperazines - chemistry ; Piperazines - metabolism ; Piperazines - pharmacology ; Protein Conformation ; Rats ; Receptors, Adrenergic, alpha-1 - chemistry ; Receptors, Adrenergic, alpha-1 - genetics ; Receptors, Adrenergic, alpha-1 - metabolism ; Signal Transduction - drug effects ; Structure-Activity Relationship ; α1-Adrenergic antagonists</subject><ispartof>European journal of medicinal chemistry, 2016-10, Vol.122, p.601-610</ispartof><rights>2016 Elsevier Masson SAS</rights><rights>Copyright © 2016 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c277t-dfde5bed92856f02fbe1a201e841bc1903e4cc90c98b45fb6b816fac389aa7f83</citedby><cites>FETCH-LOGICAL-c277t-dfde5bed92856f02fbe1a201e841bc1903e4cc90c98b45fb6b816fac389aa7f83</cites><orcidid>0000-0001-5679-0820</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejmech.2016.06.052$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3549,27923,27924,45994</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27448917$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Silva, Renata Oliveira</creatorcontrib><creatorcontrib>de Oliveira, Andressa Souza</creatorcontrib><creatorcontrib>Nunes Lemes, Laís Flávia</creatorcontrib><creatorcontrib>de Camargo Nascente, Luciana</creatorcontrib><creatorcontrib>Coelho do Nascimento Nogueira, Patrícia</creatorcontrib><creatorcontrib>Silveira, Edilberto R.</creatorcontrib><creatorcontrib>Brand, Guilherme D.</creatorcontrib><creatorcontrib>Vistoli, Giulio</creatorcontrib><creatorcontrib>Cilia, Antonio</creatorcontrib><creatorcontrib>Poggesi, Elena</creatorcontrib><creatorcontrib>Buccioni, Michela</creatorcontrib><creatorcontrib>Marucci, Gabriella</creatorcontrib><creatorcontrib>Bolognesi, Maria Laura</creatorcontrib><creatorcontrib>Romeiro, Luiz Antonio Soares</creatorcontrib><title>Synthesis and structure–activity relationships of novel arylpiperazines as potent antagonists of α1-adrenoceptor</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>Arylpiperazines 2–11 were synthesized, and their biological profiles at α1-adrenergic receptors (α1-ARs) assessed by binding assays in CHO cells expressing human cloned subtypes and by functional experiments in isolated rat vas deferens (α1A), spleen (α1B), and aorta (α1D). Modifications at the 1,3-benzodioxole and phenyl phamacophoric units resulted in the identification of a number of potent compounds (moderately selective with respect to the α1b-AR), in binding experiments. Notably, compound 7 (LDT451) showed a subnanomolar pKi of 9.41 towards α1a-AR. An encouragingly lower α1B-potency was a general trend for all the series of compounds, which showed α1A/D over α1B selectivity in functional assays. If adequately optimized, such peculiar selectivity could have relevance for a potential LUTS/BPH therapeutic application.
[Display omitted]
•11 new phenylpiperazines derived from LASSBio 772 has been designed and synthesized.•Affinities for human α1-AR subtypes in radioligand binding assays were assessed.•Antagonist profiles at α1-AR subtypes in functional bioassays were evaluated.•Among the newly synthesized compounds, potent ligands were identified.•SAR-analysis identified new hits for further search for improved α1-AR agents.</description><subject>Adrenergic alpha-1 Receptor Antagonists - chemical synthesis</subject><subject>Adrenergic alpha-1 Receptor Antagonists - chemistry</subject><subject>Adrenergic alpha-1 Receptor Antagonists - metabolism</subject><subject>Adrenergic alpha-1 Receptor Antagonists - pharmacology</subject><subject>Adrenergic receptors subtypes</subject><subject>Animals</subject><subject>Arylpiperazines</subject><subject>BPH</subject><subject>Cell Line, Tumor</subject><subject>Chemistry Techniques, Synthetic</subject><subject>CHO Cells</subject><subject>Cloning, Molecular</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Drug Design</subject><subject>Humans</subject><subject>Male</subject><subject>Molecular Docking Simulation</subject><subject>Muscle, Smooth, Vascular - cytology</subject><subject>Muscle, Smooth, Vascular - drug effects</subject><subject>Piperazines - chemical synthesis</subject><subject>Piperazines - chemistry</subject><subject>Piperazines - metabolism</subject><subject>Piperazines - pharmacology</subject><subject>Protein Conformation</subject><subject>Rats</subject><subject>Receptors, Adrenergic, alpha-1 - chemistry</subject><subject>Receptors, Adrenergic, alpha-1 - genetics</subject><subject>Receptors, Adrenergic, alpha-1 - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Structure-Activity Relationship</subject><subject>α1-Adrenergic antagonists</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1qHDEQhUVwyIwnuYExvfSmx5L6T70xGOPEAUMWTtZCrS5lNPRIbZV6YLzyHXISXySH8EkiZ8ZeGooqCl7V432EnDC6ZJTV5-slrDegV0uetiVNVfEPZM6aWuQFr8ojMqecF3nFi3JGjhHXlNKqpvQTmfGmLEXLmjnBu52LK0CLmXJ9hjFMOk4Bnh__KB3t1sZdFmBQ0XqHKzti5k3m_BaGTIXdMNoRgnqwDtI9ZqOP4GL6FNVv7yzG__K_TyxXfQDnNYzRh8_ko1EDwpfDXJBfX69_Xt3ktz--fb-6vM01b5qY96aHqoO-5aKqDeWmA6ZSWBAl6zRraQGl1i3VrejKynR1J1htlC5Eq1RjRLEgZ_u_Y_D3E2CUG4sahkE58BNKJlhV1DVPfUHKvVQHjxjAyDHYTUooGZUvuOVa7nHLF9ySpkpgF-T04DB1G-jfjl75JsHFXgAp59ZCkKgtOA29DaCj7L193-EfXRKYgg</recordid><startdate>20161021</startdate><enddate>20161021</enddate><creator>Silva, Renata Oliveira</creator><creator>de Oliveira, Andressa Souza</creator><creator>Nunes Lemes, Laís Flávia</creator><creator>de Camargo Nascente, Luciana</creator><creator>Coelho do Nascimento Nogueira, Patrícia</creator><creator>Silveira, Edilberto R.</creator><creator>Brand, Guilherme D.</creator><creator>Vistoli, Giulio</creator><creator>Cilia, Antonio</creator><creator>Poggesi, Elena</creator><creator>Buccioni, Michela</creator><creator>Marucci, Gabriella</creator><creator>Bolognesi, Maria Laura</creator><creator>Romeiro, Luiz Antonio Soares</creator><general>Elsevier Masson SAS</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-5679-0820</orcidid></search><sort><creationdate>20161021</creationdate><title>Synthesis and structure–activity relationships of novel arylpiperazines as potent antagonists of α1-adrenoceptor</title><author>Silva, Renata Oliveira ; de Oliveira, Andressa Souza ; Nunes Lemes, Laís Flávia ; de Camargo Nascente, Luciana ; Coelho do Nascimento Nogueira, Patrícia ; Silveira, Edilberto R. ; Brand, Guilherme D. ; Vistoli, Giulio ; Cilia, Antonio ; Poggesi, Elena ; Buccioni, Michela ; Marucci, Gabriella ; Bolognesi, Maria Laura ; Romeiro, Luiz Antonio Soares</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c277t-dfde5bed92856f02fbe1a201e841bc1903e4cc90c98b45fb6b816fac389aa7f83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adrenergic alpha-1 Receptor Antagonists - chemical synthesis</topic><topic>Adrenergic alpha-1 Receptor Antagonists - chemistry</topic><topic>Adrenergic alpha-1 Receptor Antagonists - metabolism</topic><topic>Adrenergic alpha-1 Receptor Antagonists - pharmacology</topic><topic>Adrenergic receptors subtypes</topic><topic>Animals</topic><topic>Arylpiperazines</topic><topic>BPH</topic><topic>Cell Line, Tumor</topic><topic>Chemistry Techniques, Synthetic</topic><topic>CHO Cells</topic><topic>Cloning, Molecular</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Drug Design</topic><topic>Humans</topic><topic>Male</topic><topic>Molecular Docking Simulation</topic><topic>Muscle, Smooth, Vascular - cytology</topic><topic>Muscle, Smooth, Vascular - drug effects</topic><topic>Piperazines - chemical synthesis</topic><topic>Piperazines - chemistry</topic><topic>Piperazines - metabolism</topic><topic>Piperazines - pharmacology</topic><topic>Protein Conformation</topic><topic>Rats</topic><topic>Receptors, Adrenergic, alpha-1 - chemistry</topic><topic>Receptors, Adrenergic, alpha-1 - genetics</topic><topic>Receptors, Adrenergic, alpha-1 - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Structure-Activity Relationship</topic><topic>α1-Adrenergic antagonists</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Silva, Renata Oliveira</creatorcontrib><creatorcontrib>de Oliveira, Andressa Souza</creatorcontrib><creatorcontrib>Nunes Lemes, Laís Flávia</creatorcontrib><creatorcontrib>de Camargo Nascente, Luciana</creatorcontrib><creatorcontrib>Coelho do Nascimento Nogueira, Patrícia</creatorcontrib><creatorcontrib>Silveira, Edilberto R.</creatorcontrib><creatorcontrib>Brand, Guilherme D.</creatorcontrib><creatorcontrib>Vistoli, Giulio</creatorcontrib><creatorcontrib>Cilia, Antonio</creatorcontrib><creatorcontrib>Poggesi, Elena</creatorcontrib><creatorcontrib>Buccioni, Michela</creatorcontrib><creatorcontrib>Marucci, Gabriella</creatorcontrib><creatorcontrib>Bolognesi, Maria Laura</creatorcontrib><creatorcontrib>Romeiro, Luiz Antonio Soares</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Silva, Renata Oliveira</au><au>de Oliveira, Andressa Souza</au><au>Nunes Lemes, Laís Flávia</au><au>de Camargo Nascente, Luciana</au><au>Coelho do Nascimento Nogueira, Patrícia</au><au>Silveira, Edilberto R.</au><au>Brand, Guilherme D.</au><au>Vistoli, Giulio</au><au>Cilia, Antonio</au><au>Poggesi, Elena</au><au>Buccioni, Michela</au><au>Marucci, Gabriella</au><au>Bolognesi, Maria Laura</au><au>Romeiro, Luiz Antonio Soares</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and structure–activity relationships of novel arylpiperazines as potent antagonists of α1-adrenoceptor</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2016-10-21</date><risdate>2016</risdate><volume>122</volume><spage>601</spage><epage>610</epage><pages>601-610</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>Arylpiperazines 2–11 were synthesized, and their biological profiles at α1-adrenergic receptors (α1-ARs) assessed by binding assays in CHO cells expressing human cloned subtypes and by functional experiments in isolated rat vas deferens (α1A), spleen (α1B), and aorta (α1D). Modifications at the 1,3-benzodioxole and phenyl phamacophoric units resulted in the identification of a number of potent compounds (moderately selective with respect to the α1b-AR), in binding experiments. Notably, compound 7 (LDT451) showed a subnanomolar pKi of 9.41 towards α1a-AR. An encouragingly lower α1B-potency was a general trend for all the series of compounds, which showed α1A/D over α1B selectivity in functional assays. If adequately optimized, such peculiar selectivity could have relevance for a potential LUTS/BPH therapeutic application.
[Display omitted]
•11 new phenylpiperazines derived from LASSBio 772 has been designed and synthesized.•Affinities for human α1-AR subtypes in radioligand binding assays were assessed.•Antagonist profiles at α1-AR subtypes in functional bioassays were evaluated.•Among the newly synthesized compounds, potent ligands were identified.•SAR-analysis identified new hits for further search for improved α1-AR agents.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>27448917</pmid><doi>10.1016/j.ejmech.2016.06.052</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-5679-0820</orcidid></addata></record> |
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| ispartof | European journal of medicinal chemistry, 2016-10, Vol.122, p.601-610 |
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| subjects | Adrenergic alpha-1 Receptor Antagonists - chemical synthesis Adrenergic alpha-1 Receptor Antagonists - chemistry Adrenergic alpha-1 Receptor Antagonists - metabolism Adrenergic alpha-1 Receptor Antagonists - pharmacology Adrenergic receptors subtypes Animals Arylpiperazines BPH Cell Line, Tumor Chemistry Techniques, Synthetic CHO Cells Cloning, Molecular Cricetinae Cricetulus Drug Design Humans Male Molecular Docking Simulation Muscle, Smooth, Vascular - cytology Muscle, Smooth, Vascular - drug effects Piperazines - chemical synthesis Piperazines - chemistry Piperazines - metabolism Piperazines - pharmacology Protein Conformation Rats Receptors, Adrenergic, alpha-1 - chemistry Receptors, Adrenergic, alpha-1 - genetics Receptors, Adrenergic, alpha-1 - metabolism Signal Transduction - drug effects Structure-Activity Relationship α1-Adrenergic antagonists |
| title | Synthesis and structure–activity relationships of novel arylpiperazines as potent antagonists of α1-adrenoceptor |
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