Design and Synthesis of New Bifunctional Sigma‑1 Selective Ligands with Antioxidant Activity
Herein we report the synthesis of new bifunctional sigma-1 (σ1)-selective ligands with antioxidant activity. To achieve this goal, we combined the structure of lipoic acid, a universal antioxidant, with an appropriate sigma aminic moiety. Ligands 14 and 26 displayed high affinity and selectivity for...
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| Veröffentlicht in: | Journal of medicinal chemistry 2013-03, Vol.56 (6), p.2447-2455 |
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| container_end_page | 2455 |
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| container_issue | 6 |
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| container_title | Journal of medicinal chemistry |
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| creator | Prezzavento, O Arena, E Parenti, C Pasquinucci, L Aricò, G Scoto, G. M Grancara, S Toninello, A Ronsisvalle, S |
| description | Herein we report the synthesis of new bifunctional sigma-1 (σ1)-selective ligands with antioxidant activity. To achieve this goal, we combined the structure of lipoic acid, a universal antioxidant, with an appropriate sigma aminic moiety. Ligands 14 and 26 displayed high affinity and selectivity for σ1 receptors (K iσ1 = 1.8 and 5.5 nM; K iσ2/σ1 = 354 and 414, respectively). Compound 26 exhibited in vivo antiopioid effects on kappa opioid (KOP) receptor-mediated analgesia. In rat liver and brain mitochondria (RLM, RBM), this compound significantly reduced the swelling and the oxidation of thiol groups induced by calcium ions. Our results demonstrate that the tested compound has protective effects against oxidative stress. |
| doi_str_mv | 10.1021/jm3017893 |
| format | Article |
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Our results demonstrate that the tested compound has protective effects against oxidative stress.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm3017893</identifier><identifier>PMID: 23470245</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Antioxidants - chemical synthesis ; Antioxidants - chemistry ; Antioxidants - metabolism ; Antioxidants - pharmacology ; Brain - cytology ; Chemistry Techniques, Synthetic ; Drug Design ; Ligands ; Liver - cytology ; Male ; Mitochondria - drug effects ; Mitochondria - metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, sigma - metabolism ; Sigma-1 Receptor ; Substrate Specificity ; Thioctic Acid - chemical synthesis ; Thioctic Acid - chemistry ; Thioctic Acid - metabolism ; Thioctic Acid - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2013-03, Vol.56 (6), p.2447-2455</ispartof><rights>Copyright © 2013 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-4dcf8e55fabde496fbb9436b5c70f59f845f1a1de2ec617e19beea91dc58af5b3</citedby><cites>FETCH-LOGICAL-a315t-4dcf8e55fabde496fbb9436b5c70f59f845f1a1de2ec617e19beea91dc58af5b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm3017893$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm3017893$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23470245$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Prezzavento, O</creatorcontrib><creatorcontrib>Arena, E</creatorcontrib><creatorcontrib>Parenti, C</creatorcontrib><creatorcontrib>Pasquinucci, L</creatorcontrib><creatorcontrib>Aricò, G</creatorcontrib><creatorcontrib>Scoto, G. M</creatorcontrib><creatorcontrib>Grancara, S</creatorcontrib><creatorcontrib>Toninello, A</creatorcontrib><creatorcontrib>Ronsisvalle, S</creatorcontrib><title>Design and Synthesis of New Bifunctional Sigma‑1 Selective Ligands with Antioxidant Activity</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Herein we report the synthesis of new bifunctional sigma-1 (σ1)-selective ligands with antioxidant activity. To achieve this goal, we combined the structure of lipoic acid, a universal antioxidant, with an appropriate sigma aminic moiety. Ligands 14 and 26 displayed high affinity and selectivity for σ1 receptors (K iσ1 = 1.8 and 5.5 nM; K iσ2/σ1 = 354 and 414, respectively). Compound 26 exhibited in vivo antiopioid effects on kappa opioid (KOP) receptor-mediated analgesia. In rat liver and brain mitochondria (RLM, RBM), this compound significantly reduced the swelling and the oxidation of thiol groups induced by calcium ions. Our results demonstrate that the tested compound has protective effects against oxidative stress.</description><subject>Animals</subject><subject>Antioxidants - chemical synthesis</subject><subject>Antioxidants - chemistry</subject><subject>Antioxidants - metabolism</subject><subject>Antioxidants - pharmacology</subject><subject>Brain - cytology</subject><subject>Chemistry Techniques, Synthetic</subject><subject>Drug Design</subject><subject>Ligands</subject><subject>Liver - cytology</subject><subject>Male</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, sigma - metabolism</subject><subject>Sigma-1 Receptor</subject><subject>Substrate Specificity</subject><subject>Thioctic Acid - chemical synthesis</subject><subject>Thioctic Acid - chemistry</subject><subject>Thioctic Acid - metabolism</subject><subject>Thioctic Acid - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkLtOAzEQRS0EIiFQ8APIDRIUC37uowzhKUVQBFpWXu84cbQPWO8S0vEL_CJfgqOEVFSjmXvmFgehY0ouKGH0cl5yQqM44TuoTyUjgYiJ2EV9QhgLWMh4Dx04NyeEcMr4PuoxLiLChOyj12twdlphVeV4sqzamV8drg1-hAW-sqardGvrShV4Yqel-vn6pngCBfjrB-CxnfpHhxe2neFh5clPm6uqxcNVbtvlIdozqnBwtJkD9HJ78zy6D8ZPdw-j4ThQnMo2ELk2MUhpVJaDSEKTZYngYSZ1RIxMTCykoYrmwECHNAKaZAAqobmWsTIy4wN0tu59a-r3DlybltZpKApVQd25lHJGoyRkMvbo-RrVTe1cAyZ9a2ypmmVKSbrSmW51evZkU9tlJeRb8s-fB07XgNIunddd4025f4p-Ab33fX4</recordid><startdate>20130328</startdate><enddate>20130328</enddate><creator>Prezzavento, O</creator><creator>Arena, E</creator><creator>Parenti, C</creator><creator>Pasquinucci, L</creator><creator>Aricò, G</creator><creator>Scoto, G. 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M</au><au>Grancara, S</au><au>Toninello, A</au><au>Ronsisvalle, S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design and Synthesis of New Bifunctional Sigma‑1 Selective Ligands with Antioxidant Activity</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2013-03-28</date><risdate>2013</risdate><volume>56</volume><issue>6</issue><spage>2447</spage><epage>2455</epage><pages>2447-2455</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Herein we report the synthesis of new bifunctional sigma-1 (σ1)-selective ligands with antioxidant activity. To achieve this goal, we combined the structure of lipoic acid, a universal antioxidant, with an appropriate sigma aminic moiety. Ligands 14 and 26 displayed high affinity and selectivity for σ1 receptors (K iσ1 = 1.8 and 5.5 nM; K iσ2/σ1 = 354 and 414, respectively). 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| subjects | Animals Antioxidants - chemical synthesis Antioxidants - chemistry Antioxidants - metabolism Antioxidants - pharmacology Brain - cytology Chemistry Techniques, Synthetic Drug Design Ligands Liver - cytology Male Mitochondria - drug effects Mitochondria - metabolism Rats Rats, Sprague-Dawley Receptors, sigma - metabolism Sigma-1 Receptor Substrate Specificity Thioctic Acid - chemical synthesis Thioctic Acid - chemistry Thioctic Acid - metabolism Thioctic Acid - pharmacology |
| title | Design and Synthesis of New Bifunctional Sigma‑1 Selective Ligands with Antioxidant Activity |
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