Increased rigidity and bioisosteric replacement in the design, synthesis and preliminary evaluation of novel, functionalized 3,3-dialkyl-γ-butyrolactones as sigma-2 ligands

Martin WR, Eades CE, Thompson JA, Huppler RE. The effects of morphine and nalorphine-like drugs in the non-dependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther. 1976;197:517–32

CAS  PubMed  Google Scholar 

Bowen WD, de Costa BR, Hellewell SB, Walker JM, Rice KC. [3H]-(+)-Pentazocine: a potent and highly selective benzomorphan-based probe for sigma-1 receptors. Mol Neuropharmacol. 1993;3:117–26

CAS  Google Scholar 

Hellewell SB, Bowen WD. A sigma-like binding site in rat pheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain. Brain Res. 1990;527:244–53. https://doi.org/10.1016/0006-8993(90)91143-5

Article  CAS  PubMed  Google Scholar 

Alon A, Schmidt HR, Wood MD, Sahn JJ, Martin SF, Krusea AC. Identification of the gene that codes for the σ2 receptor. Proc. Natl. Acad. Sci. USA. 2017;114:7160–5. https://doi.org/10.1073/pnas.1705154114

Article  CAS  PubMed  PubMed Central  Google Scholar 

Alon A, Lyu J, Braz JM, Tummino TA, Craik V, O’Meara MJ, Webb CM, Radchenko DS, Moroz YS, Huang XP, Liu Y, Roth BL, Irwin JJ, Basbaum AI, Shoichet BK, Kruse AC. Structures of the σ2 receptor enable docking for bioactive ligand discovery. Nature. 2021;600:759–64. https://doi.org/10.1038/s41586-021-04175-x

Article  CAS  PubMed  PubMed Central  Google Scholar 

Son KN, Lee H, Shah D, Kalmodia S, Miller RC, Ali M, Balasubramaniam A, Cologna SM, Kong H, Shukla D, Aakalu VK. Histatin-1 is an endogenous ligand of the sigma-2 receptor. FEBS J. 2021;288:6815–27. https://doi.org/10.1111/febs.16108

Article  CAS  PubMed  Google Scholar 

Ebrahimi-Fakhar D, Wahlster L, Bartz F, Werenbeck-Ueding J, Praggastis M, Zhang J, Joggerst-Thomalla B, Theiss S, Grimm D, Ory DS, Runz H. Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells. Hum Mol Genet. 2016;25:3588–99. https://doi.org/10.1093/hmg/ddw204

Article  CAS  Google Scholar 

Sorbi C, Belluti S, Atene CG, Marocchi F, Linciano P, Roy N, Paradiso E, Casarini L, Ronsisvalle S, Zanocco-Marani T, Brasili L, Lanfrancone L, Imbriano C, Di Rocco G, Franchini S. BS148 Reduces the Aggressiveness of Metastatic Melanoma via Sigma-2 Receptor Targeting. Int J Mol Sci. 2023;24:9684. https://doi.org/10.3390/ijms24119684

Article  CAS  PubMed  PubMed Central  Google Scholar 

Abatematteo FS, Niso M, Lacivita E, Abate C. σ2 Receptor and Its Role in Cancer with Focus on a MultiTarget Directed Ligand (MTDL) Approach. Molecules. 2021;26:3743

Article  CAS  PubMed  PubMed Central  Google Scholar 

Shoghi KI, Xu J, Su Y, He J, Rowland D, Yan Y, Garbow JR, Tu Z, Jones LA, Higashikubo R, Wheeler KT, Lubet RA, Mach RH, You M. Quantitative receptor-based imaging of tumor proliferation with the sigma-2 ligand [(18)F]ISO-1. PLoS One. 2013;8:e74188. https://doi.org/10.1371/journal.pone.0074188

Article  CAS  PubMed  PubMed Central  Google Scholar 

McDonald ES, Doot RK, Young AJ, Schubert EK, Tchou J, Pryma DA, Farwell MD, Nayak A, Ziober A, Feldman MD, DeMichele A, Clark AS, Shah PD, Lee H, Carlin SD, Mach RH, Mankoff DA. Breast Cancer 18F-ISO-1 Uptake as a Marker of Proliferation Status. J Nucl Med. 2020;61:665–70. https://doi.org/10.2967/jnumed.119.232363

Article  CAS  PubMed  PubMed Central  Google Scholar 

Li Y, Xie X, Liao S, Zeng Z, Li S, Xie B, Huang Q, Zhou H, Zhou C, Lin J, Huang Y, Xu D. A011, a novel small-molecule ligand of σ2 receptor, potently suppresses breast cancer progression via endoplasmic reticulum stress and autophagy. Biomed Pharmacother. 2022;152:113232. https://doi.org/10.1016/j.biopha.2022.113232

Article  CAS  PubMed  Google Scholar 

Sahn JJ, Mejia GL, Ray PR, Martin SF, Price TJ. Sigma 2 Receptor/Tmem97 Agonists Produce Long Lasting Antineuropathic Pain Effects in Mice. ACS Chem Neurosci. 2017;8:1801–11. https://doi.org/10.1021/acschemneuro.7b00200

Article  CAS  PubMed  Google Scholar 

Wilson LL, Alleyne AR, Eans SO, Cirino TJ, Stacy HM, Mottinelli M, Intagliata S, McCurdy CR, McLaughlin JP. Characterization of CM-398, a Novel Selective Sigma-2 Receptor Ligand, as a Potential Therapeutic for Neuropathic Pain. Molecules. 2022;27:3617. https://doi.org/10.3390/molecules27113617

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rishton GM, Look GC, Ni ZJ, Zhang J, Wang Y, Huang Y, Wu X, Izzo NJ, LaBarbera KM, Limegrover CS, Rehak C, Yurko R, Catalano SM. Discovery of Investigational Drug CT1812, an Antagonist of the Sigma-2 Receptor Complex for Alzheimer’s Disease. ACS Med Chem Lett. 2021;12:1389–95. https://doi.org/10.1021/acsmedchemlett.1c00048

Article  CAS  PubMed  PubMed Central  Google Scholar 

Limegrover CS, Yurko R, Izzo NJ, LaBarbera KM, Rehak C, Look G, Rishton G, Safferstein H, Catalano SM. Sigma-2 receptor antagonists rescue neuronal dysfunction induced by Parkinson’s patient brain-derived α-synuclein. J Neurosci Res. 2021;99:1161–76. https://doi.org/10.1002/jnr.24782. https://clinicaltrials.gov/ct2/show/NCT04735536?term=CT1812&draw=2&rank=1

Vázquez-Rosa E, Watson MR, Sahn JJ, Hodges TR, Schroeder RE, Cintrón-Pérez CJ, Shin MK, Yin TC, Emery JL, Martin SF, Liebl DJ, Pieper AA. Neuroprotective Efficacy of a Sigma 2 Receptor/TMEM97 Modulator (DKR-1677) after Traumatic Brain Injury. ACS Chem Neurosci. 2019;10:1595–602. https://doi.org/10.1021/acschemneuro.8b00543

Article  CAS  PubMed  Google Scholar 

Guo L, Zhen X. Sigma-2 receptor ligands: neurobiological effects. Curr Med Chem. 2015;22:989–1003. https://doi.org/10.2174/0929867322666150114163607

Article  CAS  PubMed  Google Scholar 

Intagliata S, Alsharif WF, Mesangeau C, Fazio N, Seminerio M, Xu YT, Matsumoto RR, McCurdy CR. Benzimidazolone-based selective σ2 receptor ligands: Synthesis and pharmacological evaluation. Eur J Med Chem. 2019;165:250–7. https://doi.org/10.1016/j.ejmech.2019.01.019

Article  CAS  PubMed  PubMed Central  Google Scholar 

Blass BE, Gao R, Blattner KM, Gordon JC, Pippin DA, Canney DJ. Design, synthesis, and evaluation of novel, selective γ-butyrolactones sigma-2 ligands. Med Chem Res. 2021;30:1713–27. https://doi.org/10.1007/s00044-021-02771-0

Article  CAS  Google Scholar 

Blass BE, Basic Principles of Drug Discovery and Development second edition, Academic Press, 2021, 5, 257–303. https://doi.org/10.1016/B978-0-12-817214-8.00005-1

Blass BE, Blattner KM, Gordon JC, Elokely KM, Pippin DA, Canney DJ. Discovery of selective, functionalized 5-(2-(5-arylhexahydropyrrolo[3,4-c]pyrrol-2(1h)-yl)ethyl)-gama-butyrolactone sigma-2 ligands. Tetrahedron Lett. 2009;50:5914–6

Google Scholar 

Canney DJ, Blass BE, Gao R, Abou-Ghabia M. Novel 5-hydroxytryptamine receptor 7 activity modulators and their method of use, WO2014164756, 2014

Canney DJ, Blass BE, Blattner KM. 5-Hydroxytryptamine receptor 7 modulators and their use as therapeutic agents, WO2018175190, 2018

Cheng HC. The power issue: determination of KB or Ki from IC50. A closer look at the Cheng-Prusoff equation, the Schild plot and related power equations. J Pharmacol Toxicol Methods. 2001;46:61–71

Article  CAS  PubMed  Google Scholar 

Yang J, Jamei M, Yeo KR, Rostami-Hodjegan A, Tucker GT. “Misuse of the well-stirred model of hepatic drug clearance.”. Drug Metab Disposition. 2007;35:501–2

Article  CAS  Google Scholar 

McMasters DR, Torres RA, Crathern SJ, Dooney D, Nachbar RB, Sheridan RP, Korzekwa KR. Inhibition of recombinant cytochrome P450 isoforms 2D6 and 2C9 by diverse drug-like molecules. J Med Chem. 2007;50:3205–13. https://doi.org/10.1021/jm0700060

Article  CAS  PubMed  PubMed Central  Google Scholar 

Comments (0)

No login
gif