Examination of the Novel Sigma-1 Receptor Antagonist, SI 1/28, for Antinociceptive and Anti-allodynic Efficacy against Multiple Types of Nociception with Fewer Liabilities of Use
Lisa L. Wilson,Shainnel O. Eans,Insitar Ramadan-Siraj,Maria N. Modica,Giuseppe Romeo,Sebastiano Intagliata,Jay P. McLaughlin +6 more
TLDR
SI 1/28 proved efficacious in the treatment of acute inflammatory pain and chronic neuropathy without liabilities at therapeutic doses, supporting the development of S1R antagonists as therapeutics for chronic pain.Abstract:
Neuropathic pain is a significant problem with few effective treatments lacking adverse effects. The sigma-1 receptor (S1R) is a potential therapeutic target for neuropathic pain, as antagonists for this receptor effectively ameliorate pain in both preclinical and clinical studies. The current research examines the antinociceptive and anti-allodynic efficacy of SI 1/28, a recently reported benzylpiperazine derivative and analog of the S1R antagonist SI 1/13, that was 423-fold more selective for S1R over the sigma-2 receptor (S2R). In addition, possible liabilities of respiration, sedation, and drug reinforcement caused by SI 1/28 have been evaluated. Inflammatory and chemical nociception, chronic nerve constriction injury (CCI) induced mechanical allodynia, and adverse effects of sedation in a rotarod assay, conditioned place preference (CPP), and changes in breath rate and locomotor activity were assessed after i.p. administration of SI 1/28. Pretreatment with SI 1/28 produced dose-dependent antinociception in the formalin test, with an ED50 (and 95% C.I.) value of 13.2 (7.42–28.3) mg/kg, i.p. Likewise, SI 1/28 produced dose-dependent antinociception against visceral nociception and anti-allodynia against CCI-induced neuropathic pain. SI 1/28 demonstrated no impairment of locomotor activity, conditioned place preference, or respiratory depression. In summary, SI 1/28 proved efficacious in the treatment of acute inflammatory pain and chronic neuropathy without liabilities at therapeutic doses, supporting the development of S1R antagonists as therapeutics for chronic pain.read more
Citations
More filters
Journal ArticleDOI
Discovery of RC-752, a Novel Sigma-1 Receptor Antagonist with Antinociceptive Activity: A Promising Tool for Fighting Neuropathic Pain
Giacomo Rossino,Ann Marie Marra,Roberta Listro,Marco Peviani,E.C. Poggio,Daniela Curti,Giorgia Pellavio,Umberto Laforenza,Giulio Dondio,Dirk Schepmann,Bernhard Wünsch,Martina Bedeschi,Noemi Marino,Anna Tesei,Hee-Jin Ha,Young Ho Kim,Ji Hun Ann,Jeewoo Lee,Pasquale Linciano,Marcello Di Giacomo,Daniela Rossi,Simona Collina +21 more
TL;DR: In this article , a series of sigma-1 receptor (S1R) antagonists based on a 2-aryl-4-aminobutanol scaffold were synthesized and evaluated in two animal models of neuropathic pain.
Journal ArticleDOI
Bispecific sigma-1 receptor antagonism and mu-opioid receptor partial agonism: WLB-73502, an analgesic with improved efficacy and safety profile compared to strong opioids
Alba Vidal-Torres,Begoña Fernández-Pastor,Mónica García,Eva Ayet,Anna Cabot,Javier Burgueño,Xavier Monroy,Bertrand Aubel,Xavier Codony,Luz Romero,Rosalia Pascual,Maria Teresa Serafini,G Encina,Carmen Almansa,Daniel Zamanillo,Manuel Merlos,José Miguel Vela +16 more
TL;DR: WLB-73502 as mentioned in this paper is a dual bispecific compound that binds sigma-1 (S1R) and mu-opioid (MOR) receptors.
Journal ArticleDOI
Structure-activity relationships of mixed σ1R/σ2R ligands with antiproliferative and anticancer effects.
Antonino N. Fallica,Valeria Ciaffaglione,Maria N. Modica,Valeria Pittalà,Loredana Salerno,Emanuele Amata,Agostino Marrazzo,Giuseppe Romeo,Sebastiano Intagliata +8 more
TL;DR: In this paper , the structure-activity relationships of structurally diverse mixed σ1R/σ2R ligands that showed promising antitumor profiles towards a variety of cancer cell lines were described.
References
More filters
Journal ArticleDOI
A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man.
Gary J. Bennett,Y.-K. Xie +1 more
TL;DR: A peripheral mononeuropathy was produced in adult rats by placing loosely constrictive ligatures around the common sciatic nerve and the postoperative behavior of these rats indicated that hyperalgesia, allodynia and, possibly, spontaneous pain were produced.
Journal ArticleDOI
Genome-wide atlas of gene expression in the adult mouse brain
Ed S. Lein,Michael Hawrylycz,Nancy Ao,Mikael Ayres,Amy Bensinger,Amy Bernard,Andrew F. Boe,Mark S. Boguski,Mark S. Boguski,Kevin S. Brockway,Emi J. Byrnes,Lin Chen,Li Chen,Tsuey-Ming Chen,Mei Chi Chin,Jimmy Chong,Brian E. Crook,Aneta Czaplinska,Chinh Dang,Suvro Datta,Nick Dee,Aimee L. Desaki,Tsega Desta,Ellen Diep,Tim A. Dolbeare,Matthew J. Donelan,Hong-Wei Dong,Jennifer G. Dougherty,Ben J. Duncan,Amanda Ebbert,Gregor Eichele,Lili K. Estin,Casey Faber,Benjamin A.C. Facer,Rick Fields,Shanna R. Fischer,Tim P. Fliss,Cliff Frensley,Sabrina N. Gates,Katie J. Glattfelder,Kevin R. Halverson,Matthew R. Hart,John G. Hohmann,Maureen P. Howell,Darren P. Jeung,Rebecca A. Johnson,Patrick T. Karr,Reena Kawal,Jolene Kidney,Rachel H. Knapik,Chihchau L. Kuan,James H. Lake,Annabel R. Laramee,Kirk D. Larsen,Christopher Lau,Tracy Lemon,Agnes J. Liang,Ying Liu,Lon T. Luong,Jesse Michaels,Judith J. Morgan,Rebecca J. Morgan,Marty Mortrud,Nerick Mosqueda,Lydia Ng,Randy Ng,Geralyn J. Orta,Caroline C. Overly,Tu H. Pak,Sheana Parry,Sayan Dev Pathak,Owen C. Pearson,Ralph B. Puchalski,Zackery L. Riley,Hannah R. Rockett,Stephen A. Rowland,Joshua J. Royall,Marcos J. Ruiz,Nadia R. Sarno,Katherine Schaffnit,Nadiya V. Shapovalova,Taz Sivisay,Clifford R. Slaughterbeck,Simon Smith,Kimberly A. Smith,Bryan I. Smith,Andy J. Sodt,Nick N. Stewart,Kenda-Ruth Stumpf,Susan M. Sunkin,Madhavi Sutram,Angelene Tam,Carey D. Teemer,Christina Thaller,Carol L. Thompson,Lee R. Varnam,Axel Visel,Axel Visel,Ray M. Whitlock,Paul Wohnoutka,Crissa K. Wolkey,Victoria Y. Wong,Matthew J.A. Wood,Murat B. Yaylaoglu,Rob Young,Brian L. Youngstrom,Xu Feng Yuan,Bin Zhang,Theresa A. Zwingman,Allan R. Jones +109 more
TL;DR: An anatomically comprehensive digital atlas containing the expression patterns of ∼20,000 genes in the adult mouse brain is described, providing an open, primary data resource for a wide variety of further studies concerning brain organization and function.
Journal Article
The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog.
TL;DR: It has been shown that buprenorphine is a partial agonist of the mu type which both suppressed and precipitated abstinence in the morphine-dependent dog while morphine and propoxyphene are stronger agonists.
Journal ArticleDOI
Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis.
Nanna B. Finnerup,Nadine Attal,Simon Haroutounian,Ewan D McNicol,Ralf Baron,Robert H. Dworkin,Ian Gilron,Maija Haanpää,Per Hansson,Per Hansson,Troels S. Jensen,Troels S. Jensen,Peter R. Kamerman,Karen Lund,Andrew Moore,Srinivasa N. Raja,Andrew S.C. Rice,Andrew S.C. Rice,Michael C. Rowbotham,Emily S. Sena,Emily S. Sena,Philip J. Siddall,Philip J. Siddall,Blair H. Smith,Mark S. Wallace +24 more
TL;DR: The results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain and allow a strong recommendation for use and proposal as first-line treatment in neuropathicPain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin.
Journal ArticleDOI
Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research.
TL;DR: 1.2 Provide an accurate summary of the background, res principal findings, and conclusions of the study.