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Medicinal Chemistry: New Chemical Classes and Subtype-Selective Ligands

  • Chapter
Sigma Receptors

6. Summary

Over the past decade, advances have been made in discovering novel σ receptor probes and developing structure-activity relationships for σ1 and σ2 receptor selectivity. These compounds have provided useful tools to further investigate the physiological role that central and peripheral σ receptors play. Furthermore, many of these compounds have been investigated for their in vivo actions, and particularly promising is their ability to attenuate cocaine-induced behaviors such as locomotor stimulation and conditioned place preference, as well as cocaine-induced toxicities. These in vivo studies are described in other chapters in this book and the interested reader is referred to these. Compounds that have dual actions at both σ1 receptors and the dopamine transporter may prove to be a novel strategy for the development of a cocaine-abuse medication and is being investigated toward this goal. Compounds selective at σ2 receptors may be useful as antineoplastic agents or for control of cell survival in neurodegenerative disease. The design and synthesis of novel and selective σ1 and σ2 receptor selective agonists and antagonists will undoubtedly provide the required molecular tools to elucidate both structure and function of these receptors.

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References

  1. Izhak Y. Sigma Receptors. Academic Press, San Diego 1994.

    Google Scholar 

  2. Walker JM, Bowen WD, Walker FO, Matsumoto RR, de Costa BR, Rice KC. Sigma receptors: biology and function. Pharmacol Rev 1990, 42:355–402.

    PubMed  CAS  Google Scholar 

  3. de Costa BR, Rothman RB, Bowen WD, Radesca L, Band L, Reid A, Paolo LD, Walker JM, Jacobson AE, Rice KC. Novel kappa opioid receptor and sigma ligands. NIDA Research Monograph 1992b, 119:76–80.

    PubMed  Google Scholar 

  4. Martin WR, Eades CE, Thompson JA, Huppler RE. The effects of morphine-and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 1976, 197 517–524.

    PubMed  CAS  Google Scholar 

  5. May EL, Jaconson AE, Mattson MV, Traynor JR, Woods JH, Harris LS, Bowman ER, Aceto MD. Synthesis and in vitro and in vivo activity of (-)-(lR,5R,9R)-and (+)-(lS,5S,9S)-N-alkenyl-,-N-alkynyl-, and-N-cyanoalkly-5,9-dimethyl-2’-hydroxy-6,7-benzomorphan homologues. J Med Chem 2000, 43:5030–5036.

    Article  PubMed  CAS  Google Scholar 

  6. Su TP. Evidence for sigma opioid receptor: binding of [3H]SKF 10,047 to etorphine-inaccessible sites in guinea-pig brain. J Pharmacol Exp Ther 1982, 223:284–290.

    PubMed  CAS  Google Scholar 

  7. Tam SW and Cook L. Sigma opiates and certain antipsychotic drugs mutually inhibit (+)-I3H]SKF 10,047 and [3H]haloperidol binding in guinea pig brain membranes. Proc Natl Acad Sci USA 1984, 81:5618–5621.

    Article  PubMed  CAS  Google Scholar 

  8. Largent BL, Gundlach AL, Snyder SH. Pharmacological and autoradiographic discrimination of sigma and phencyclidine receptor binding sites in brain with (+)-[3h]SKF 10,047, (+)-[3H]-3-[3-hydroxy-phenyl]-N-(l-propyl)piperidine and [3H]-1-[1-(2-thienyl)cyclohexyI]-piperidine. J Pharmacol Exp Ther 1986, 238:739–748.

    PubMed  CAS  Google Scholar 

  9. Weber E, Sonders M, Quarum M, McLean S, Pou S, Keana JF. 1,3-Di(2-[5-3h]tolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs. Proc Natl Acad Sci USA 1986, 83:8784–8788.

    Article  PubMed  CAS  Google Scholar 

  10. de Costa BR, Bowen WD, Hellewell SB, Walker JM, Thurkauf A, Jacobson AE, Rice KC. Synthesis and evaluation of optically pure [3H](+)-pentazocine, a highly potent and selective radioligand for sigma receptors. FEBS Lett 1989, 251:53–58.

    Article  PubMed  Google Scholar 

  11. Hanner M, Moebius FF, Flandorfer A, Knaus HG, Striessnig J, Kempner E, Glossmann H. Purification, molecular cloning, and expression of the mammalian sigma,-binding site. Proc Natl Acad Sci USA 1996, 93:8072–8077.

    Article  PubMed  CAS  Google Scholar 

  12. Ronsisvalle G, Prezzavento 0, Marrazzo A, Vittorio F, Massimino M, Murari G, Spampinato S. Synthesis of (+)-cis-N-(4-isothiocyanatobenzyl)-N-normetazocine, an isothiocyanate derivative of N-benzylnormetazocine as acylant agent for the sigma-1 receptor. J Med Chem 2002, 45:2662–2665.

    Article  PubMed  CAS  Google Scholar 

  13. 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, 527:244–253.

    Article  PubMed  CAS  Google Scholar 

  14. Quirion R, Bowen WD, Itzhak Y, Junien JL, Musacchio JM, Rothman RB, Su TP, Tam SW, Taylor DP. A proposal for the classification of sigma binding sites. Trends Pharmacol Sci 1992, 13:85–86.

    Article  PubMed  CAS  Google Scholar 

  15. Hellewell SB, Bruce A, Feinstein G, Orringer J, Williams W, Bowen WD. Rat liver and kidney contain high densities of sigma-1 and sigma-2 receptors: characterization by ligand binding and photoaffinity labeling. Eur J Pharmacol Mol Pharmacol Sect 1994, 268:9–18.

    Article  CAS  Google Scholar 

  16. 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, 3:117–126.

    CAS  Google Scholar 

  17. Ablordeppey SY, Fischer JB, Burke Howie KJ, Glennon RA. Design, synthesis and binding of sigma receptor ligands derived from butaclamol. Med Chem Res 1992, 2:368–375.

    CAS  Google Scholar 

  18. Contreras PC, DiMaggio DA, O’Donohue TL. An endogenous ligand for the sigmaopioid binding site. Synapse 1987, 157–61.

    Google Scholar 

  19. Su TP, Weissman AD, Yeh SY. Endogenous Ligands for sigma opioid receptors in the brain (“sigmaphin”): evidence from binding assays. Life Sci 1986, 38:299–2210.

    Google Scholar 

  20. Neumaier JF, Chavkin C. Calcium-dependent displacement of haloperidol-sensitive sigma receptor binding in rat hippocampal slices following tissue depolarization. Brain Res 1989, 500:215–222.

    Article  PubMed  CAS  Google Scholar 

  21. Connor MA, Chavkin C. Focal stimulation of specific pathways in the rat hippocampus causes a reduction in radioligand binding to the haloperidol-sensitive sigma receptor. Exp Brain Res 1991, 85:528–536.

    Article  PubMed  CAS  Google Scholar 

  22. Su TP, London ED, Jaffe JH. Steroid binding at sigma receptors suggests a link between endocrine, nervous, and immune systems. Science 1988, 240:219–221.

    Article  PubMed  CAS  Google Scholar 

  23. Moebius FF, Reiter RJ, Hanner M, Glossmann H. High affinity of sigma-1 binding sites for sterol isomerization inhibitors: Evidence for a pharmacological relationship with the yeast sterol C8-C7 isomerase. Br J Pharmacol 1997, 121: 1–6.

    Article  PubMed  CAS  Google Scholar 

  24. de Costa BR, Radesca L, Paolo LD, Bowen WD. Synthesis, characterization, and biological evaluation of a novel class of N-(arylethy1)-N-alkyl-2-(1-pyrrolidinyl)ethylamines. J Med Chem 1992a 35:38–47.

    Article  PubMed  Google Scholar 

  25. Zhang Y, Williams W, Bowen WD, Rice KC. Synthesis and evaluation of arylsubstituted N-(arylethyl)-N-methyl-2-(1-pyrrolidinyl)ethylamines and corresponding arylacetamides for sigma receptor affinity. J Med Chem 1996, 39:3564–3568.

    Article  PubMed  CAS  Google Scholar 

  26. Ronsisvalle G, Marrazzo A, Prezzavento 0, Pasquinucci L, Vittorio F, Pittala V, Pappalardo MS, Cacciaguerra S, Spampinato S. (+)-cis-N-Ethyleneamino-Nnormetazocine derivatives. Novel and selective sigma ligands with antagonist properties. J Med Chem 1998, 41: 1574–1580.

    Article  PubMed  CAS  Google Scholar 

  27. El-Ashmawy M, Ablordeppey SY, Issa H, Gad L, Fischer JB, Burke Howie KJ, Glennon RA. Further investigation of 5-phenylpentylamine derivatives as novel sigma receptor ligands. Med Chem Res 1992:2119–2126.

    Google Scholar 

  28. Maeda DY, Williams W, Bowen WD, Coop A. A Sigma-1 receptor selective analogue of BD1008. A potential substitute for (+)-opioids in sigma receptor binding assays. Bioorg Med Chem Lett 2000, 10: 17–18.

    Article  PubMed  CAS  Google Scholar 

  29. Berardi F, Loiodice F, Fracchiolla G, Colabufo NA, Perrone R, Tortorella V. Synthesis of chiral l-[o-(4-chlorophenoxy)alkyl]-4-methylpiperindines and their biological evaluation at sigma-I, sigma-2, and sterol &A7 isomerase sites. J Med Chem 2003, 46:2117–2124.

    Article  PubMed  CAS  Google Scholar 

  30. Bowen WD, Moses EL, Tolentino PJ, Walker JM. Metabolites of haloperidol display preferential activity at sigma receptors compared to dopamine D-2 receptors. Eur J Pharmacol 1990, l77:111–118.

    Article  Google Scholar 

  31. Guitart X, Ballarin M, Codony X, Dordal A, Farre AJ, Frigola J, Merce R. E-5842. Drugs Fut 1999, 24:386–392.

    Article  CAS  Google Scholar 

  32. Huang YS, Hammond PS, Whirret PR, Kuhner RJ, Wu L, Childers SR, Mach RH. Synthesis and quantitative structure-activity relationships of N-(1-benzylpiperidin-4-yl) phenylacetamides and related analogues as potent and selective sigma-1 receptor ligands. J Med Chem 1998, 41:2361–2370.

    Article  PubMed  CAS  Google Scholar 

  33. Huang Y, Hammond PS, Wu L, Mach RH. Synthesis and structure-activity relationships of N-(1-benzylpiperidin-4-y1)arylacetamide analogues as potent sigma-1 receptor ligands. J Med Chem 2001, 44:4404–4415.

    Article  PubMed  CAS  Google Scholar 

  34. Nakazato A, Ohta K, Sekiguchi Y, Okuyama S, Chaki S, Kawashima Y, Hatayame K. Design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine sigma ligands as potential antipsychotic drugs. J Med Chem 1999a, 42: 1076–1087.

    Article  PubMed  CAS  Google Scholar 

  35. Nakazato A, Kumagai T, Ohta K, Chaki S, Okuyama S, Tomisawa K. Synthesis and SAR of 1-Alkyl-2-phenethylamine derivatives designed from N,N-dipropyl-4-methoxy 3-(2-pheny1ethoxy)phenethylamine to discover sigma-1 ligands. J Med Chem 1999b, 42:3965–3970.

    Article  PubMed  CAS  Google Scholar 

  36. Bowen WD, Bertha, CM, Vilner BJ, Rice KC. CB-64D and CB-184: Ligands with high sigma-2 receptor affinity and subtype selectivity. Eur J Pharmacol 1995a, 278:257–260.

    Article  PubMed  CAS  Google Scholar 

  37. Maeda DY, Williams W, Kim WE, Thatcher LN, Bowen WD, Coop A. NArylalkylpiperidines as high affinity sigma-1 and sigma-2 receptor ligands: phenylpropylamines as potential leads for selective sigma-2 agents. Bioorg Med Chem Lett 2002, 12:497–500.

    Article  PubMed  CAS  Google Scholar 

  38. Vilner BJ, Bowen WD. Modulation of cellular calcium by sigma-2 receptors: release from intercelluar stores in human SK-N-SH neuroblastoma cells. J Pharmacol Exp Ther 2000, 292: 900–911.

    PubMed  CAS  Google Scholar 

  39. Crawford KW, Bowen WD. Sigma-2 receptor agonists activate a novel apoptotic pathway and potentiate antineoplastic drugs in breast tumor cell lines. Cancer Res 2002, 62:313–322.

    PubMed  CAS  Google Scholar 

  40. Crawford KW, Coop A, Bowen WD. Sigma-2 receptors regulate changes in sphingolipid levels in breast tumor cells. Eur J Pharmacol2002, 443:207–209.

    Article  PubMed  CAS  Google Scholar 

  41. Bowen WD, Vilner BJ, Williams W, Bertha CM, Kuehne ME, Jaconson AE. Ibogaine and its congeners are sigma-2 receptor-selective ligands with moderate affinity. Eur J Pharmacol 1995b, 279:Rl–R3.

    Article  Google Scholar 

  42. Bowen WD. Sigma receptors and iboga alkaloids. Alkaloids Chem Biol 2001, 56:173–191.

    PubMed  CAS  Google Scholar 

  43. Mach RH, Vangveravong S, Huang Y, Yang B, Blair JB, Wu L. Synthesis of Nsubstituted 9-azabicyclo[3.3.l]nonan-30.-yl phenylcarbamate analogs as sigma-2 receptor ligands. Med Chem Res 2003, 11:380–398.

    Google Scholar 

  44. Mach RH, Wu L, West T, Whirrett BR, Childers SR. The analgesic tropane analogue (+/-)-SM 21 has a high affinity for sigma-2 receptors. Life Sci 1999, 64:PL131–PL137.

    Article  PubMed  CAS  Google Scholar 

  45. Matsumoto RR, Mack AL. (+/-)-SM 21 attenuates the convulsive and locomotor stimulatory effects of cocaine. Eur J Pharmacol2001, 417:Rl–R2.

    Article  Google Scholar 

  46. Sharkey J, Glen KA, Wolfe S, Kuhar MJ. Cocaine binding at sigma receptors. Eur J Pharmacol 1988, 149: 171–174.

    Article  PubMed  CAS  Google Scholar 

  47. Menkel M, Terry P, Pontecorvo M, Katz JL, Witkin JM. Selective sigma ligands block stimulant effects of cocaine. Eur J Pharmacol 1991, 201:251–252.

    Article  PubMed  CAS  Google Scholar 

  48. Romieu P, Martin-Fandon R, Maurice T. Involvement of the sigma-1 receptor in the cocaine-induced conditioned place preference. Neuroreport 2000, 11:2885–2888.

    Article  PubMed  CAS  Google Scholar 

  49. Ujike H, Kuroda S, Otsuki S. Sigma receptor antagonist block the development of sensitization to cocaine. Eur J Pharmacol 1996, 296:123–128.

    Article  PubMed  CAS  Google Scholar 

  50. McCracken K, Bowen WD, De Costa BR, Matsumoto RR. Two novel sigma receptor ligands, BD1047 and LR172, attenuate cocaine-induced toxicity and locomotor activity. Eur J Pharmacol 1999a, 370:225–232.

    Article  PubMed  CAS  Google Scholar 

  51. McCracken K, Bowen W, Matsumoto RR. Novel sigma receptor ligands attenuate the locomotor stimulatory effects of cocaine. Eur J Phamacol 1999b, 365:35–38.

    Article  CAS  Google Scholar 

  52. Matsumoto RR, McCracken K, Friedman M, Pouw B, De Costa BR, Bowen WD. Conformationally restricted analogs of BD1008 and antisense oligodeoxynucleotide targeting sigma-1 receptors produce anti-cocaine effects in mice. Eur J Pharmacol2001b, 419:163–174.

    Article  PubMed  CAS  Google Scholar 

  53. Matsumoto RR, McCracken K, Pouw B, Miller J, Bowen WD, Williams W, de Costa BR. N-Alkyl substituted analogs of the sigma receptor ligand BD1008 and traditional sigma receptor ligands affect cocaine-induced convulsions and lethality in mice. Eur J Pharmacol2001c, 411:261–273.

    Article  PubMed  CAS  Google Scholar 

  54. Kahoun JR, Ruoho AE. (125I) Iodoazidococaine, a photoaffinity label for the haloperidol-sensitive sigma receptor. Proc Natl Aca Sci USA 1992, 89:1393–1397.

    Article  CAS  Google Scholar 

  55. Wilke RA, Mehta RP, Lupardus J, Chen Y, Ruoho A, Jackson MB. Sigma receptor photolabeling and sigma-receptor-mediated modulation of potassium channels in tumor cells. J Biol Chem 1999, 274: 18387–18392.

    Article  PubMed  CAS  Google Scholar 

  56. Contreras PC, Bremer ME, Rao TS. GBR-12909 and fluspirilene potently inhibited binding of [3H](+)3-PPP to sigma receptors in rat brain. Life Sci 1990, 47:133–137.

    Article  Google Scholar 

  57. Husbands SM, Izenwasser S, Loeloff RJ, Katz JL, Bowen WD, Vilner BJ, Newman AH. Isothiocyanate derivatives of 9-[3-(cis-3,5-dimethyl-l-piperazinyl)propyl]-carbazole (rimcazole): irreversible ligands for the dopamine transporter. J Med Chem 1997, 40:4340–4346.

    Article  PubMed  CAS  Google Scholar 

  58. Izenwasser S, Newman AH, Katz JL. Cocaine and several sigma receptor ligands inhibit dopamine uptake in rat caudate-putamen. Eur J Pharmacol 1993, 243:201–205.

    Article  PubMed  CAS  Google Scholar 

  59. Husbands SM, Isenwasser S, Kopajtic T, Bowen WD, Vilner BJ, Katz JL, Newman AH. Structure-activity relationships at the monoamine transporters and sigma receptors for a novel series of 9-[3-cis-3,5-dimethyI-l-piperazinyl)-propyl]cbazole (rimcazole) analogues. J Med Chem 1999, 42:4446–4455.

    Article  PubMed  CAS  Google Scholar 

  60. Cao JJ, Husbands SM, Kopajtic T, Katz JL, Newman AH. [3-cis-3,5-Dimethyl-(1-piperazinyl)alkyl]-bis-(4′-fluorophenyl)aine analogues as novel probes for the dopamine transporter. Bioorg Med Chem Lett 2001, 11:3169–3173.

    Article  PubMed  CAS  Google Scholar 

  61. Cao JJ, Kulkarni SS, Husbands SM, Bowen WD, Williams W, Kopajtic T, Katz JL, George C, Newman AH. Dual probes for the dopamine transporter and sigma-1 receptors: novel piperazinyl alkyl-bis-(4’-fluoropheny1)amine analogues as potential cocaine-abuse therapeutic agents. J Med Chem 2003, 46:2589–2598.

    Article  PubMed  CAS  Google Scholar 

  62. Matecka D, Rothman RB, Radesca L, De Costa BR, Dersch CM, Partilla JS, Pert A, Glowa JR, Woljnick FHE, Rice KC. Development of novel, potent, and selective dopamine reuptake inhibitors through alteration of piperazine ring of 1-[2(diphenylmethoxy)ethyl]-and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropy1)piperazines (GBR 12936 and GBR 12909). J Med Chem 1996, 39:4704–4716.

    Article  PubMed  CAS  Google Scholar 

  63. Matecka D, Lewis D, Rothman RB, Dersch CM, Wojnicki FHE, Glowa JR, De Vries AC, Pert A, Rice KC. Heteroaromatic analogs of I-[2-(diphenylmethoxy)ethyl]-and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as high-affinity dopamine reuptake inhibitors. J Med Chem 1997, 40:705–716.

    Article  PubMed  CAS  Google Scholar 

  64. Katz JL, Libby T, Kopajtic T, Husbands SM, Newman AH. Behavioral effects of rimcazole analogues alone and in combination with cocaine. Eur J Pharmacol 2003, 468: 109–119.

    Article  PubMed  CAS  Google Scholar 

  65. Newman AH, Kulkarni S. Probes for the dopamine transporter: new leads towards a cocaine-abuse therapeutic-A focus on analogues of benztropine and rimcazole. Med Res Rev 2002, 5:429–464.

    Article  Google Scholar 

  66. Matsumoto RR, Hewett KL, Pouw B, Bowen WD, Husbands SM, Cao JJ, Newman AH. Rimcazole analogs attenuate the convulsive effects of cocaine: correlation with binding to sigma receptors rather than dopamine transporters. Neuropharrnacology 2001a,41:878–886.

    Article  CAS  Google Scholar 

  67. Romieu P, Phan V, Martin-Fardon R, Maurice T. Involvement of the sigma-1 receptor in cocaine-induced conditioned place preference: possible dependence on dopamine uptake blockade. Neuropsychopharmacology 2002, 26:444–455.

    Article  PubMed  CAS  Google Scholar 

  68. Maurice T, Martin-Fardon R, Romieu P, Matsumoto RR. Sigma-1 receptor antagonists represent a new strategy against cocaine addiction and toxicity. Neurosci Biobehav Rev 2002, 26:499–527.

    Article  PubMed  CAS  Google Scholar 

  69. Glennon RA, Ablordeppey SY, Ismaiel AM, El-Ashmawy MB, Fischer JB, Howie KB. Structural features important for sigma-1 receptor binding. J Med Chem 1994, 37:1214–1219.

    Article  PubMed  CAS  Google Scholar 

  70. Ablordeppey SY, Fischer JB, Glennon RA. Is a nitrogen atom an important pharmacophoric element in sigma ligand binding? Bioorg Med Chem 2000, 8:2105–2111.

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Section on Medicinal Chemistry, National Institutes of Health, National Institute on Drug Abuse-Intramural Research Program, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA

    Dr. Amy Hauck Newman

  2. Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, 637 HSFII, Baltimore, MD 21201, USA

    Dr. Andrew Coop

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  1. Dr. Amy Hauck Newman
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Editors and Affiliations

  1. National Institute on Drug Abuse, Bethesda, MD

    Tsung-Ping Su

  2. University of Mississippi, University, MS

    Rae R. Matsumoto

  3. Brown University, Providence, RI

    Wayne D. Bowen

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Newman, A.H., Coop, A. (2007). Medicinal Chemistry: New Chemical Classes and Subtype-Selective Ligands. In: Su, TP., Matsumoto, R.R., Bowen, W.D. (eds) Sigma Receptors. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-36514-5_2

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