Skip to content
2000
Volume 25, Issue 12
  • ISSN: 1389-5575
  • E-ISSN: 1875-5607

Abstract

Sigma receptors (σRs), comprising σ1 and σ2 subtypes, are versatile pharmacological targets with significant roles in cancer, neurodegeneration, and psychiatric disorders. The tetrahydroisoquinoline (THIQ) scaffold, a core structure in many biologically active compounds, has garnered attention as a versatile platform for designing σRs ligands. THIQ-based compounds exhibit potent σRs binding affinity, leading to therapeutic effects ranging from neuroprotection to antitumor activity. This mini-review explores the structural features of THIQ ligands, their interaction with σRs, and their therapeutic implications. Challenges and future prospects for THIQ derivatives in σRs research are also discussed.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/mrmc/10.2174/0113895575379843250711134106
2025-07-22
2025-11-03

  • From This Site

    /content/journals/mrmc/10.2174/0113895575379843250711134106
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. LinkensK. SchmidtH.R. SahnJ.J. KruseA.C. MartinS.F. Investigating isoindoline, tetrahydroisoquinoline, and tetrahydrobenzazepine scaffolds for their sigma receptor binding properties.Eur. J. Med. Chem.201815155756710.1016/j.ejmech.2018.02.024 29656199
     [Google Scholar]
  2. FallicaA.N. PittalàV. ModicaM.N. SalernoL. RomeoG. MarrazzoA. HelalM.A. IntagliataS. Recent advances in the development of sigma receptor ligands as cytotoxic agents: A medicinal chemistry perspective.J. Med. Chem.202164127926796210.1021/acs.jmedchem.0c02265 34076441
     [Google Scholar]
  3. MartinW.R. EadesC.G. ThompsonJ.A. HupplerR.E. GilbertP.E. The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog.J. Pharmacol. Exp. Ther.1976197351753210.1016/S0022‑3565(25)30536‑7 945347
     [Google Scholar]
  4. SuT.P. Psychotomimetic opioid binding: specific binding of [3H]SKF-10047 to etorphine-inaccessible sites in guinea-pig brain.Eur. J. Pharmacol.1981751818210.1016/0014‑2999(81)90352‑6 6274661
     [Google Scholar]
  5. CHEBI:228223 - (+)-SKF-10,047.Available from: https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:228223
    [Google Scholar]
  6. HayashiT. SuT.P. Sigma-1 receptors (sigma(1) binding sites) form raft-like microdomains and target lipid droplets on the endoplasmic reticulum: roles in endoplasmic reticulum lipid compartmentalization and export.J. Pharmacol. Exp. Ther.2003306271872510.1124/jpet.103.051284 12730355
     [Google Scholar]
  7. NavarroJ.F. BeltránD. CavasM. Effects of (+) SKF 10,047, a sigma-1 receptor agonist, on anxiety, tested in two laboratory models in mice.Psicothema2012243427430 22748735
     [Google Scholar]
  8. TamS.W. CookL. Sigma opiates and certain antipsychotic drugs mutually inhibit (+)-[3H] SKF 10,047 and [3H]haloperidol binding in guinea pig brain membranes.Proc. Natl. Acad. Sci. USA198481175618562110.1073/pnas.81.17.5618 6147851
     [Google Scholar]
  9. KhazanN. YoungG.A. El-FakanyE.E. HongO. CalligaroD. Sigma receptors mediate the psychotomimetic effects of N-allylnormetazocine (SKF-10,047), but not its opioid agonistic-antagonistic properties.Neuropharmacology198423898398710.1016/0028‑3908(84)90015‑7 6090969
     [Google Scholar]
  10. HalberstadtA.L. HyunJ. RudermanM.A. PowellS.B. Effects of the psychotomimetic benzomorphan N-allylnormetazocine (SKF 10,047) on prepulse inhibition of startle in mice.Pharmacol. Biochem. Behav.2016148697510.1016/j.pbb.2016.05.009 27236030
     [Google Scholar]
  11. ChaudharyV. ChaturvediS. WadhwaA. ChaudharyR. GautamD. SharmaD. KumarR. MishraA.K. Design, development and bio-evaluation of a novel radio-ligand 99mTc-THQ-DTPA as a sigma 2 receptor specific breast tumor imaging agent.Bioorg. Med. Chem.20249711751510.1016/j.bmc.2023.117515 38043245
     [Google Scholar]
  12. HannerM. MoebiusF.F. FlandorferA. KnausH.G. StriessnigJ. KempnerE. GlossmannH. Purification, molecular cloning, and expression of the mammalian sigma1-binding site.Proc. Natl. Acad. Sci. USA199693158072807710.1073/pnas.93.15.8072 8755605
     [Google Scholar]
  13. WengT.Y. TsaiS.Y.A. SuT.P. Roles of sigma-1 receptors on mitochondrial functions relevant to neurodegenerative diseases.J. Biomed. Sci.20172417410.1186/s12929‑017‑0380‑6 28917260
     [Google Scholar]
  14. DichiaraM. AmbrosioF.A. LeeS.M. Ruiz-CanteroM.C. LombinoJ. CoricelloA. CostaG. ShahD. CostanzoG. PasquinucciL. SonK.N. CosentinoG. González-CanoR. MarrazzoA. AakaluV.K. CobosE.J. AlcaroS. AmataE. Discovery of AD258 as a sigma receptor ligand with potent antiallodynic activity.J. Med. Chem.20236616114471146310.1021/acs.jmedchem.3c00959 37535861
     [Google Scholar]
  15. MorenoE. Moreno-DelgadoD. NavarroG. HoffmannH.M. FuentesS. Rosell-VilarS. GasperiniP. Rodríguez-RuizM. MedranoM. MallolJ. CortésA. CasadóV. LluísC. FerréS. OrtizJ. CanelaE. McCormickP.J. Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine’s effects.J. Neurosci.201434103545355810.1523/JNEUROSCI.4147‑13.2014 24599455
     [Google Scholar]
  16. KimF.J. KovalyshynI. BurgmanM. NeilanC. ChienC.C. PasternakG.W. σ 1 receptor modulation of G-protein-coupled receptor signaling: potentiation of opioid transduction independent from receptor binding.Mol. Pharmacol.201077469570310.1124/mol.109.057083 20089882
     [Google Scholar]
  17. AydarE. PalmerC.P. KlyachkoV.A. JacksonM.B. The sigma receptor as a ligand-regulated auxiliary potassium channel subunit.Neuron200234339941010.1016/S0896‑6273(02)00677‑3 11988171
     [Google Scholar]
  18. NavarroG. MorenoE. BonaventuraJ. BrugarolasM. FarréD. AguinagaD. MallolJ. CortésA. CasadóV. LluísC. FerreS. FrancoR. CanelaE. McCormickP.J. Cocaine inhibits dopamine D2 receptor signaling via sigma-1-D2 receptor heteromers.PLoS One201384e6124510.1371/journal.pone.0061245 23637801
     [Google Scholar]
  19. HayashiT. SuT.P. Regulating ankyrin dynamics: Roles of sigma-1 receptors.Proc. Natl. Acad. Sci. USA200198249149610.1073/pnas.98.2.491 11149946
     [Google Scholar]
  20. JiaJ. ChengJ. WangC. ZhenX. Sigma-1 receptor-modulated neuroinflammation in neurological diseases.Front. Cell. Neurosci.20181231410.3389/fncel.2018.00314 30294261
     [Google Scholar]
  21. HuangY.S. LuH.L. ZhangL.J. WuZ. Sigma-2 receptor ligands and their perspectives in cancer diagnosis and therapy.Med. Res. Rev.201434353256610.1002/med.21297 23922215
     [Google Scholar]
  22. XuJ. ZengC. ChuW. PanF. RothfussJ.M. ZhangF. TuZ. ZhouD. ZengD. VangveravongS. JohnstonF. SpitzerD. ChangK.C. HotchkissR.S. HawkinsW.G. WheelerK.T. MachR.H. Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site.Nat. Commun.20112138010.1038/ncomms1386 21730960
     [Google Scholar]
  23. PatiM.L. GrozaD. RigantiC. KopeckaJ. NisoM. BerardiF. HagerS. HeffeterP. HiraiM. TsugawaH. KabeY. SuematsuM. AbateC. Sigma-2 receptor and progesterone receptor membrane component 1 (PGRMC1) are two different proteins: Proofs by fluorescent labeling and binding of sigma-2 receptor ligands to PGRMC1.Pharmacol. Res.2017117677410.1016/j.phrs.2016.12.023 28007569
     [Google Scholar]
  24. AlonA. SchmidtH.R. WoodM.D. SahnJ.J. MartinS.F. KruseA.C. Identification of the gene that codes for the σ2 receptor.Proc. Natl. Acad. Sci. USA2017114277160716510.1073/pnas.1705154114 28559337
     [Google Scholar]
  25. NguyenN.T. Jaramillo-MartinezV. MathewM. SureshV.V. SivaprakasamS. BhutiaY.D. GanapathyV. Sigma receptors: Novel regulators of iron/heme homeostasis and ferroptosis.Int. J. Mol. Sci.202324191467210.3390/ijms241914672 37834119
     [Google Scholar]
  26. YangK. ZengC. WangC. SunM. YinD. SunT. Sigma-2 receptor: A potential target for cancer/alzheimer’s disease treatment via its regulation of cholesterol homeostasis.Molecules20202522543910.3390/molecules25225439 33233619
     [Google Scholar]
  27. RousseauxC.G. GreeneS.F. Sigma receptors [ σ Rs]: Biology in normal and diseased states.J. Recept. Signal Transduct. Res.201536416210.3109/10799893.2015.1015737 26056947
     [Google Scholar]
  28. ScottJ.D. WilliamsR.M. Chemistry and biology of the tetrahydroisoquinoline antitumor antibiotics.Chem. Rev.200210251669173010.1021/cr010212u 11996547
     [Google Scholar]
  29. Faheem; Karan Kumar, B.; Chandra Sekhar, K.V.G.; Chander, S.; Kunjiappan, S.; Murugesan, S. Medicinal chemistry perspectives of 1,2,3,4-tetrahydroisoquinoline analogs – biological activities and SAR studies.RSC Advances20211120122541228710.1039/D1RA01480C 35423735
     [Google Scholar]
  30. KohnoM. OhtaS. HirobeM. Tetrahydroisoquinoline and 1-methyl-tetrahydroisoquinoline as novel endogenous amines in rat brain.Biochem. Biophys. Res. Commun.1986140144845410.1016/0006‑291X(86)91111‑3 3778459
     [Google Scholar]
  31. Antkiewicz-MichalukL. WąsikA. MichalukJ. 1-Methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous amine with unexpected mechanism of action: new vistas of therapeutic application.Neurotox. Res.201425111210.1007/s12640‑013‑9402‑7 23719903
     [Google Scholar]
  32. BrossiA. PeiX-F. Biological Activity of Unnatural Alkaloid Enantiomers.In: The Alkaloids: Chemistry and Biology.Elsevier199810913910.1016/S1099‑4831(08)60041‑3
     [Google Scholar]
  33. ThangeswaranD. ShamsuddinS. BalakrishnanV. A comprehensive review on the progress and challenges of tetrahydroisoquinoline derivatives as a promising therapeutic agent to treat Alzheimer’s disease.Heliyon20241010e3078810.1016/j.heliyon.2024.e30788 38803973
     [Google Scholar]
  34. TiwariR. SinghD. SinghJ. ChhillarA. ChandraR. VermaA. Synthesis, antibacterial activity and QSAR studies of 1,2-disubstituted-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines.Eur. J. Med. Chem.2006411404910.1016/j.ejmech.2005.10.010 16356593
     [Google Scholar]
  35. ZhuJ. LuJ. ZhouY. LiY. ChengJ. ZhengC. Design, synthesis, and antifungal activities in vitro of novel tetrahydroisoquinoline compounds based on the structure of lanosterol 14α-demethylase (CYP51) of fungi.Bioorg. Med. Chem. Lett.200616205285528910.1016/j.bmcl.2006.08.001 16905318
     [Google Scholar]
  36. KumarA. KatiyarS. GuptaS. ChauhanP. Syntheses of new substituted triazino tetrahydroisoquinolines and β-carbolines as novel antileishmanial agents1.Eur. J. Med. Chem.200641110611310.1016/j.ejmech.2005.09.007 16356594
     [Google Scholar]
  37. LiuX.H. ZhuJ. ZhouA. SongB.A. ZhuH.L. baiL.S. BhaduryP.S. PanC.X. Synthesis, structure and antibacterial activity of new 2-(1-(2-(substituted-phenyl)-5-methyloxazol-4-yl)-3-(2-substitued-phenyl)-4,5-dihydro-1H-pyrazol-5-yl)-7-substitued-1,2,3,4-tetrahydroisoquinoline derivatives.Bioorg. Med. Chem.20091731207121310.1016/j.bmc.2008.12.034 19147367
     [Google Scholar]
  38. SwidorskiJ.J. LiuZ. YinZ. WangT. CariniD.J. RahematpuraS. ZhengM. JohnsonK. ZhangS. LinP.F. ParkerD.D. LiW. MeanwellN.A. HamannL.G. Regueiro-RenA. Inhibitors of HIV-1 attachment: The discovery and structure–activity relationships of tetrahydroisoquinolines as replacements for the piperazine benzamide in the 3-glyoxylyl 6-azaindole pharmacophore.Bioorg. Med. Chem. Lett.201626116016710.1016/j.bmcl.2015.11.009 26584882
     [Google Scholar]
  39. EfangeN.M. LobeM.M.M. YamtheL.R.T. PekamJ.N.M. TarkangP.A. AyongL. EfangeS.M.N. Spirofused Tetrahydroisoquinoline-Oxindole Hybrids (Spiroquindolones) as potential multitarget antimalarial Agents: Preliminary hit optimization and efficacy evaluation in mice.Antimicrob. Agents Chemother.20226612e00607e0062210.1128/aac.00607‑22 36409128
     [Google Scholar]
  40. YadavP. KumarA. AlthagafiI. NemayshV. RaiR. PratapR. The recent development of tetrahydro-quinoline/isoquinoline based compounds as anticancer agents.Curr. Top. Med. Chem.202121171587162210.2174/1568026621666210526164208 34042035
     [Google Scholar]
  41. SinghI.P. ShahP. Tetrahydroisoquinolines in therapeutics: A patent review (2010-2015).Expert Opin. Ther. Pat.2017271173610.1080/13543776.2017.1236084 27623022
     [Google Scholar]
  42. VilnerB.J. BowenW.D. Modulation of cellular calcium by sigma-2 receptors: Release from intracellular stores in human SK-N-SH neuroblastoma cells.J. Pharmacol. Exp. Ther.2000292390091110.1016/S0022‑3565(24)35369‑8 10688603
     [Google Scholar]
  43. VilnerB.J. JohnC.S. BowenW.D. Sigma-1 and sigma-2 receptors are expressed in a wide variety of human and rodent tumor cell lines.Cancer Res.1995552408413 7812973
     [Google Scholar]
  44. VilnerB.J. de CostaB.R. BowenW.D. Cytotoxic effects of sigma ligands: Sigma receptor-mediated alterations in cellular morphology and viability.J. Neurosci.199515111713410.1523/JNEUROSCI.15‑01‑00117.1995 7823122
     [Google Scholar]
  45. DichiaraM. AmbrosioF.A. BarbaraciC. González-CanoR. CostaG. ParentiC. MarrazzoA. PasquinucciL. CobosE.J. AlcaroS. AmataE. Synthesis, computational insights, and evaluation of novel sigma receptors ligands.ACS Chem. Neurosci.202314101845185810.1021/acschemneuro.3c00074 37155827
     [Google Scholar]
  46. DehdashtiF. LaforestR. GaoF. ShoghiK.I. AftR.L. NussenbaumB. KreiselF.H. BartlettN.L. CashenA. Wagner-JohnsonN. MachR.H. Assessment of cellular proliferation in tumors by PET using 18F-ISO-1.J. Nucl. Med.201354335035710.2967/jnumed.112.111948 23359657
     [Google Scholar]
  47. McDonaldE.S. DootR.K. YoungA.J. SchubertE.K. TchouJ. PrymaD.A. FarwellM.D. NayakA. ZioberA. FeldmanM.D. DeMicheleA. ClarkA.S. ShahP.D. LeeH. CarlinS.D. MachR.H. MankoffD.A. Breast Cancer 18 F-ISO-1 uptake as a marker of proliferation status.J. Nucl. Med.202061566567010.2967/jnumed.119.232363 31836680
     [Google Scholar]
  48. SunY.T. WangG.F. YangY.Q. JinF. WangY. XieX.Y. MachR.H. HuangY.S. Synthesis and pharmacological evaluation of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as sigma-2 receptor ligands.Eur. J. Med. Chem.201814722723710.1016/j.ejmech.2017.11.016 29438891
     [Google Scholar]
  49. MachR.H. SmithC.R. al-NabulsiI. WhirrettB.R. ChildersS.R. WheelerK.T.Σ. Sigma 2 receptors as potential biomarkers of proliferation in breast cancer.Cancer Res.1997571156161 8988058
     [Google Scholar]
  50. WheelerK.T. WangL-M. WallenC.A. ChildersS.R. ClineJ.M. KengP.C. MachR.H. Sigma-2 receptors as a biomarker of proliferation in solid tumours.Br. J. Cancer20008261223123210.1054/bjoc.1999.1067 10735510
     [Google Scholar]
  51. ShoghiK.I. XuJ. SuY. HeJ. RowlandD. YanY. GarbowJ.R. TuZ. JonesL.A. HigashikuboR. WheelerK.T. LubetR.A. MachR.H. YouM. Quantitative receptor-based imaging of tumor proliferation with the sigma-2 ligand [(18)F]ISO-1.PLoS One201389e7418810.1371/journal.pone.0074188 24073202
     [Google Scholar]
  52. XieX.Y. LiY.Y. MaW.H. ChenA.F. SunY.T. LeeJ.Y. RiadA. XuD.H. MachR.H. HuangY.S. Synthesis, binding, and functional properties of tetrahydroisoquinolino-2-alkyl phenones as selective σ2R/TMEM97 ligands.Eur. J. Med. Chem.202120911290610.1016/j.ejmech.2020.112906 33049607
     [Google Scholar]
  53. TuZ. XuJ. JonesL.A. LiS. ZengD. KungM.P. KungH.F. MachR.H. Radiosynthesis and biological evaluation of a promising σ2-receptor ligand radiolabeled with fluorine-18 or iodine-125 as a PET/SPECT probe for imaging breast cancer.Appl. Radiat. Isot.201068122268227310.1016/j.apradiso.2010.06.004 20594864
     [Google Scholar]
  54. MachR.H. ZengC. HawkinsW.G. The σ2 receptor: A novel protein for the imaging and treatment of cancer.J. Med. Chem.201356187137716010.1021/jm301545c 23734634
     [Google Scholar]
  55. GlennonR. Pharmacophore identification for sigma-1 (sigma1) receptor binding: application of the “deconstruction-reconstruction-elaboration” approach.Mini Rev. Med. Chem.200551092794010.2174/138955705774329519 16250835
     [Google Scholar]
  56. GlennonR.A. SmithJ.D. IsmaielA.M. El-AshmawyM. BattagliaG. FischerJ.B. Identification and exploitation of the. sigma.-opiate pharmacophore.J. Med. Chem.19913431094109810.1021/jm00107a033 1848295
     [Google Scholar]
  57. IyamuI.D. LvW. MalikN. MishraR.K. SchiltzG.E. Development of tetrahydroindazole‐based potent and selective sigma‐2 receptor ligands.ChemMedChem201914131248125610.1002/cmdc.201900203 31071238
     [Google Scholar]
  58. KekudaR. PrasadP.D. FeiY.J. LeibachF.H. GanapathyV. Cloning and functional expression of the human type 1 sigma receptor (hSigmaR1).Biochem. Biophys. Res. Commun.1996229255355810.1006/bbrc.1996.1842 8954936
     [Google Scholar]
  59. SchmidtH.R. ZhengS. GurpinarE. KoehlA. ManglikA. KruseA.C. Crystal structure of the human σ1 receptor.Nature2016532760052753010.1038/nature17391 27042935
     [Google Scholar]
  60. MeyerC. SchepmannD. YanagisawaS. YamaguchiJ. Dal ColV. LauriniE. ItamiK. PriclS. WünschB. Pd-catalyzed direct C-H bond functionalization of spirocyclic σ1 ligands: Generation of a pharmacophore model and analysis of the reverse binding mode by docking into a 3D homology model of the σ1 receptor.J. Med. Chem.201255188047806510.1021/jm300894h 22913577
     [Google Scholar]
  61. AbateC. MosierP.D. BerardiF. GlennonR.A.A. A structure-affinity and comparative molecular field analysis of Sigma-2 (Σ2).Receptor Ligands. Cent Nerv Syst. Agents Med. Chem.2009924610.2174/1871524910909030246
     [Google Scholar]
  62. AlonA. LyuJ. BrazJ.M. TumminoT.A. CraikV. O’MearaM.J. WebbC.M. RadchenkoD.S. MorozY.S. HuangX.P. LiuY. RothB.L. IrwinJ.J. BasbaumA.I. ShoichetB.K. KruseA.C. Structures of the σ2 receptor enable docking for bioactive ligand discovery.Nature2021600789075976410.1038/s41586‑021‑04175‑x 34880501
     [Google Scholar]
  63. LauriniE. ZampieriD. MamoloM.G. VioL. ZanetteC. FlorioC. PosoccoP. FermegliaM. PriclS. A 3D-pharmacophore model for σ2 receptors based on a series of substituted benzo[d]oxazol-2(3H)-one derivatives.Bioorg. Med. Chem. Lett.20102092954295710.1016/j.bmcl.2010.03.009 20347592
     [Google Scholar]
  64. BaiS. LiS. XuJ. PengX. SaiK. ChuW. TuZ. ZengC. MachR.H. Synthesis and structure-activity relationship studies of conformationally flexible tetrahydroisoquinolinyl triazole carboxamide and triazole substituted benzamide analogues as σ2 receptor ligands.J. Med. Chem.201457104239425110.1021/jm5001453 24821398
     [Google Scholar]
  65. YangD. ComeauA. BowenW.D. MachR.H. RossB.D. HongH. Van DortM.E. Design and investigation of a [ 18 F]-labeled benzamide derivative as a high affinity dual sigma receptor subtype radioligand for prostate tumor imaging.Mol. Pharm.201714377078010.1021/acs.molpharmaceut.6b01020 28135101
     [Google Scholar]
  66. ChristmannU. DíazJ.L. PascualR. BordasM. ÁlvarezI. MonroyX. PorrasM. YesteS. ReinosoR.F. MerlosM. VelaJ.M. AlmansaC. Discovery of WLB-89462, a new drug-like and highly selective σ 2 receptor ligand with neuroprotective properties.J. Med. Chem.20236617124991251910.1021/acs.jmedchem.3c01060 37607512
     [Google Scholar]
  67. MésangeauC. AmataE. AlsharifW. SeminerioM.J. RobsonM.J. MatsumotoR.R. PoupaertJ.H. McCurdyC.R. Synthesis and pharmacological evaluation of indole-based sigma receptor ligands.Eur. J. Med. Chem.201146105154516110.1016/j.ejmech.2011.08.031 21899931
     [Google Scholar]
  68. NisoM. AbateC. ContinoM. FerorelliS. AzzaritiA. PerroneR. ColabufoN.A. BerardiF. Sigma-2 receptor agonists as possible antitumor agents in resistant tumors: hints for collateral sensitivity.ChemMedChem20138122026203510.1002/cmdc.201300291 24106081
     [Google Scholar]
  69. MachR.H. HuangY. FreemanR.A. WuL. VangveravongS. LuedtkeR.R. Conformationally-flexible benzamide analogues as dopamine D3 and σ2 receptor ligands.Bioorg. Med. Chem. Lett.200414119520210.1016/j.bmcl.2003.09.083 14684327
     [Google Scholar]
  70. ZampieriD. RomanoM. FortunaS. AmataE. DichiaraM. CosentinoG. MarrazzoA. MamoloM.G. Design, synthesis, and cytotoxic assessment of new haloperidol analogues as potential anticancer compounds targeting sigma receptors.Molecules20242911269710.3390/molecules29112697 38893570
     [Google Scholar]
  71. MaedaD.Y. WilliamsW. KimW.E. ThatcherL.N. BowenW.D. CoopA. N-arylalkylpiperidines as high-affinity sigma-1 and sigma-2 receptor ligands: phenylpropylamines as potential leads for selective sigma-2 agents.Bioorg. Med. Chem. Lett.200212349750010.1016/S0960‑894X(01)00788‑0 11814827
     [Google Scholar]
  72. HajipourA.R. GuoL.W. PalA. MavlyutovT. RuohoA.E. Electron-donating para-methoxy converts a benzamide-isoquinoline derivative into a highly Sigma-2 receptor selective ligand.Bioorg. Med. Chem.201119247435744010.1016/j.bmc.2011.10.046 22055714
     [Google Scholar]
  73. AshfordM.E. NguyenV.H. GreguricI. PhamT.Q. KellerP.A. KatsifisA. Synthesis and in vitro evaluation of tetrahydroisoquinolines with pendent aromatics as sigma-2 (σ2) selective ligands.Org. Biomol. Chem.201412578379410.1039/C3OB42254B 24306445
     [Google Scholar]
  74. ZampieriD. FortunaS. CalabrettiA. RomanoM. MenegazziR. SchepmannD. WünschB. CollinaS. ZanonD. MamoloM.G. Discovery of new potent dual sigma receptor/GluN2b ligands with antioxidant property as neuroprotective agents.Eur. J. Med. Chem.201918026828210.1016/j.ejmech.2019.07.012 31319263
     [Google Scholar]
  75. KimH.Y. LeeJ.Y. HsiehC.J. RiadA. IzzoN.J. CatalanoS.M. GrahamT.J.A. MachR.H. Screening of σ 2 receptor ligands and In vivo Evaluation of 11 C-Labeled 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline for potential use as a σ 2 receptor brain PET Tracer.J. Med. Chem.20226586261627210.1021/acs.jmedchem.2c00191 35404616
     [Google Scholar]
  76. WangL. YeJ. HeY. Deuther-ConradW. ZhangJ. ZhangX. CuiM. SteinbachJ. HuangY. BrustP. JiaH. 18 F-Labeled indole-based analogs as highly selective radioligands for imaging sigma-2 receptors in the brain.Bioorg. Med. Chem.201725143792380210.1016/j.bmc.2017.05.019 28549890
     [Google Scholar]
  77. XieF. KniessT. NeuberC. Deuther-ConradW. MamatC. LiebermanB.P. LiuB. MachR.H. BrustP. SteinbachJ. PietzschJ. JiaH. Novel indole-based sigma-2 receptor ligands: Synthesis, structure–affinity relationship and antiproliferative activity.MedChemComm2015661093110310.1039/C5MD00079C
     [Google Scholar]
  78. ZampieriD. LauriniE. VioL. FermegliaM. PriclS. WünschB. SchepmannD. MamoloM.G. Improving selectivity preserving affinity: New piperidine-4-carboxamide derivatives as effective sigma-1-ligands.Eur. J. Med. Chem.20159079780810.1016/j.ejmech.2014.12.018 25528334
     [Google Scholar]
  79. BergkemperM. SchepmannD. WünschB. Synthesis of σ Receptor ligands with a spirocyclic system connected with a tetrahydroisoquinoline moiety via different linkers.ChemMedChem20211671184119710.1002/cmdc.202000861 33332704
     [Google Scholar]
  80. WuZ.W. SongS.Y. LiL. LuH.L. LiebermanB. HuangY.S. MachR.H. Synthesis and evaluation of tetrahydroindazole derivatives as sigma-2 receptor ligands.Bioorg. Med. Chem.20152371463147110.1016/j.bmc.2015.02.012 25752422
     [Google Scholar]
/content/journals/mrmc/10.2174/0113895575379843250711134106
Loading
Exploring Tetrahydroisoquinoline (THIQ) Scaffold as Therapeutic Modulators of Sigma Receptors
Mini Rev Med Chem 25, 951 (2025); https://doi.org/10.2174/0113895575379843250711134106
/content/journals/mrmc/10.2174/0113895575379843250711134106
/content/journals/mrmc/10.2174/0113895575379843250711134106
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): pharmacophore; SAR; Sigma receptors; tetrahydroisoquinoline; σ1R; σ2R

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test