Derrida Today最新文献

Large library docking for cannabinoid-1 receptor agonists with reduced side effects. 大型文库对接，寻找可减少副作用的大麻素-1 受体激动剂。

Derrida Today Pub Date : 2024-02-28 DOI: 10.1101/2023.02.27.530254

Tia A Tummino, Christos Iliopoulos-Tsoutsouvas, Joao M Braz, Evan S O'Brien, Reed M Stein, Veronica Craik, Ngan K Tran, Suthakar Ganapathy, Fangyu Liu, Yuki Shiimura, Fei Tong, Thanh C Ho, Dmytro S Radchenko, Yurii S Moroz, Sian Rodriguez Rosado, Karnika Bhardwaj, Jorge Benitez, Yongfeng Liu, Herthana Kandasamy, Claire Normand, Meriem Semache, Laurent Sabbagh, Isabella Glenn, John J Irwin, Kaavya Krishna Kumar, Alexandros Makriyannis, Allan I Basbaum, Brian K Shoichet

{"title":"Large library docking for cannabinoid-1 receptor agonists with reduced side effects.","authors":"Tia A Tummino, Christos Iliopoulos-Tsoutsouvas, Joao M Braz, Evan S O'Brien, Reed M Stein, Veronica Craik, Ngan K Tran, Suthakar Ganapathy, Fangyu Liu, Yuki Shiimura, Fei Tong, Thanh C Ho, Dmytro S Radchenko, Yurii S Moroz, Sian Rodriguez Rosado, Karnika Bhardwaj, Jorge Benitez, Yongfeng Liu, Herthana Kandasamy, Claire Normand, Meriem Semache, Laurent Sabbagh, Isabella Glenn, John J Irwin, Kaavya Krishna Kumar, Alexandros Makriyannis, Allan I Basbaum, Brian K Shoichet","doi":"10.1101/2023.02.27.530254","DOIUrl":"10.1101/2023.02.27.530254","url":null,"abstract":"Large library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking new agonists for the cannabinoid-1 receptor (CB1R), we docked 74 million tangible molecules, prioritizing 46 high ranking ones for de novo synthesis and testing. Nine were active by radioligand competition, a 20% hit-rate. Structure-based optimization of one of the most potent of these (Ki = 0.7 uM) led to '4042, a 1.9 nM ligand and a full CB1R agonist. A cryo-EM structure of the purified enantiomer of '4042 ('1350) in complex with CB1R-Gi1 confirmed its docked pose. The new agonist was strongly analgesic, with generally a 5-10-fold therapeutic window over sedation and catalepsy and no observable conditioned place preference. These findings suggest that new cannabinoid chemotypes may disentangle characteristic cannabinoid side-effects from their analgesia, supporting the further development of cannabinoids as pain therapeutics.","PeriodicalId":42836,"journal":{"name":"Derrida Today","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10849508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74092979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Life, Would That it Might Be To Say – Power, Metaphor, Tragen, Épuis(s)ement 生活，它可能会说-权力，隐喻，Tragen， Épuis(s)ement

Derrida Today Pub Date : 2023-11-01 DOI: 10.3366/drt.2023.0315

Naomi Waltham-Smith

{"title":"Life, Would That it Might Be To Say – Power, Metaphor, Tragen, Épuis(s)ement","authors":"Naomi Waltham-Smith","doi":"10.3366/drt.2023.0315","DOIUrl":"https://doi.org/10.3366/drt.2023.0315","url":null,"abstract":"In Insister – À Jacques Derrida Cixous declares that she will have to write ‘the book of words’, among which ‘words of power’ will be vermögen (to be able), together with Unvermöglickeit (impossibility), and tragen (to carry), along with austragen (to bear to term) and übertragen (to transfer, translate, also in the sense of metaphor). By examining Derrida's reading of Cixous in H. C. pour la vie, c'est à dire … this article deepens the association of tragen with life and power that fascinates Derrida in the second year of his final seminar where he tracks a thread between Austrag, Walten, Trieb, and Vermögen. Its point of departure is a passage towards the end of H. C. pour la vie where Derrida speaks of the trap of metalanguage or, rather, metaphrasis that lurks in the c’est of c'est à dire. I link this passage both to the discussion of metaphorization in the earlier ‘Le puits et la pyramide’ and the characterization of puisse as ‘the exhaustion [ l'épuisement] of the sun before its time’ in the essay on Cixous to associate puissance with the wearing-out of the world and its usure in the double sense elaborated in ‘La mythologie blanche’.","PeriodicalId":42836,"journal":{"name":"Derrida Today","volume":"375 3","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135111277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Epic of Genesis: Catherine Malabou and the gêne of Epigenetics 创世纪的史诗:凯瑟琳·马拉布和gêne的表观遗传学

Derrida Today Pub Date : 2023-11-01 DOI: 10.3366/drt.2023.0311

Jonathan Basile

引用次数: 0

Artificial Life, Feeling Machines, and the Text of Deconstruction 人工生命、感觉机器与解构主义文本

Derrida Today Pub Date : 2023-11-01 DOI: 10.3366/drt.2023.0313

Adam R. Rosenthal

引用次数: 0

General Editor's Note 总编注

Derrida Today Pub Date : 2023-11-01 DOI: 10.3366/drt.2023.0310

Nicole Anderson