Skip to main content
SpringerLink
Log in

Synthesis and Pharmacological Characterization of a Novel Sigma Receptor Ligand with Improved Metabolic Stability and Antagonistic Effects Against Methamphetamine

  • Research Article
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

Methamphetamine interacts with sigma receptors at physiologically relevant concentrations suggesting a potential site for pharmacologic intervention. In the present study, a previous sigma receptor ligand, CM156, was optimized for metabolic stability, and the lead analog was evaluated against the behavioral effects of methamphetamine. Radioligand binding studies demonstrated that the lead analog, AZ66, displayed high nanomolar affinity for both sigma-1 and sigma-2 receptors (2.4 ± 0.63 and 0.51 ± 0.15, respectively). In addition, AZ66 had preferential affinity for sigma receptors compared to seven other sites and a significantly longer half-life than its predecessor, CM156, in vitro and in vivo. Pretreatment of male, Swiss Webster mice with intraperitoneal (10–20 mg/kg) or oral (20–30 mg/kg) dosing of AZ66 significantly attenuated the acute locomotor stimulatory effects of methamphetamine. Additionally, AZ66 (10–20 mg/kg, i.p.) significantly reduced the expression and development of behavioral sensitization induced by repeated methamphetamine administration. Taken together, these data indicate that sigma receptors can be targeted to mitigate the acute and subchronic behavioral effects of methamphetamine and AZ66 represents a viable lead compound in the development of novel therapeutics against methamphetamine-induced behaviors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Romanelli F, Smith KM. Clinical effects and management of methamphetamine abuse. Pharmacotherapy. 2006;26:1148–56.

    Article  PubMed  CAS  Google Scholar 

  2. Cadet JL, Krasnova IN. Molecular bases of methamphetamine-induced neurodegeneration. Int Rev Neurobiol. 2009;88:101–19.

    Article  PubMed  CAS  Google Scholar 

  3. Lan KC, Lin YF, Yu FC, Lin CS, Chu P. Clinical manifestations and prognostic features of acute methamphetamine intoxication. J Formos Med Assoc. 1998;97:528–33.

    PubMed  CAS  Google Scholar 

  4. Volkow ND, Chang L, Wang GJ, Fowler JS, Franceschi D, Sedler M, Gatley SJ, Miller E, Hitzemann R, Ding YS, Logan J. Loss of dopamine transporters in methamphetamine abusers recovers with protracted abstinence. J Neurosci. 2001;21:9414–8.

    PubMed  CAS  Google Scholar 

  5. Karila L, Weinstein A, Aubin HJ, Benyamina A, Reynaud M, Batki SL. Pharmacological approaches to methamphetamine dependence: a focused review. Br J Clin Pharmacol. 2010;69:578–92.

    Article  PubMed  CAS  Google Scholar 

  6. Hanner M, Moebius FF, Flandorfer A, Knaus HG, Striessnig J, Kempner E, Glossmann H. Purification, molecular cloning, and expression of the mammalian sigma1-binding site. Proc Natl Acad Sci U S A. 1996;93:8072–7.

    Article  PubMed  CAS  Google Scholar 

  7. Hayashi T, Su TP. Intracellular dynamics of sigma-1 receptors (σ(1) binding sites) in NG108-15 cells. J Pharmacol Exp Ther. 2003;306:726–33.

    Article  PubMed  CAS  Google Scholar 

  8. Hayashi T, Su TP. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell. 2007;131:596–610.

    Article  PubMed  CAS  Google Scholar 

  9. Hayashi T, Maurice T, Su TP. Ca2+ signaling via sigma(1)-receptors: novel regulatory mechanism affecting intracellular Ca2+ concentration. J Pharmacol Exp Ther. 2000;293:788–98.

    PubMed  CAS  Google Scholar 

  10. Booth RG, Baldessarini RJ. (+)-6,7-Benzomorphan sigma ligands stimulate dopamine synthesis in rat corpus striatum tissue. Brain Res. 1991;557:349–52.

    Article  PubMed  CAS  Google Scholar 

  11. Bergeron R, Debonnel G, De Montigny C. Modification of the N-methyl-D-aspartate response by antidepressant sigma receptor ligands. Eur J Pharmacol. 1993;240:319–23.

    Article  PubMed  CAS  Google Scholar 

  12. Gronier B, Debonnel G. Involvement of sigma receptors in the modulation of the glutamatergic/NMDA neurotransmission in the dopaminergic systems. Eur J Pharmacol. 1999;368:183–96.

    Article  PubMed  CAS  Google Scholar 

  13. Aydar E, Palmer CP, Klyachko VA, Jackson MB. The sigma receptor as a ligand-regulated auxiliary potassium channel subunit. Neuron. 2002;34:399–410.

    Article  PubMed  CAS  Google Scholar 

  14. Vilner BJ, de Costa BR, Bowen WD. Cytotoxic effects of sigma ligands: sigma receptor-mediated alterations in cellular morphology and viability. J Neurosci. 1995;15:117–34.

    PubMed  CAS  Google Scholar 

  15. Vilner BJ, Bowen WD. Modulation of cellular calcium by sigma-2 receptors: release from intracellular stores in human SK-N-SH neuroblastoma cells. J Pharmacol Exp Ther. 2000;292:900–11.

    PubMed  CAS  Google Scholar 

  16. 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;62:313–22.

    PubMed  CAS  Google Scholar 

  17. Crawford KW, Coop A, Bowen WD. σ(2) Receptors regulate changes in sphingolipid levels in breast tumor cells. Eur J Pharmacol. 2002;443:207–9.

    Article  PubMed  CAS  Google Scholar 

  18. Nguyen EC, McCracken KA, Liu Y, Pouw B, Matsumoto RR. Involvement of sigma (σ) receptors in the acute actions of methamphetamine: receptor binding and behavioral studies. Neuropharmacology. 2005;49:638–45.

    Article  PubMed  CAS  Google Scholar 

  19. Itzhak Y. Repeated methamphetamine-treatment alters brain sigma receptors. Eur J Pharmacol. 1993;230:243–4.

    Article  PubMed  CAS  Google Scholar 

  20. Hayashi T, Justinova Z, Hayashi E, Cormaci G, Mori T, Tsai SY, Barnes C, Goldberg SR, Su TP. Regulation of sigma-1 receptors and endoplasmic reticulum chaperones in the brain of methamphetamine self-administering rats. J Pharmacol Exp Ther. 2010;332:1054–63.

    Article  PubMed  CAS  Google Scholar 

  21. Ujike H, Okumura K, Zushi Y, Akiyama K, Otsuki S. Persistent supersensitivity of sigma receptors develops during repeated methamphetamine treatment. Eur J Pharmacol. 1992;211:323–8.

    Article  PubMed  CAS  Google Scholar 

  22. Takahashi S, Miwa T, Horikomi K. Involvement of sigma 1 receptors in methamphetamine-induced behavioral sensitization in rats. Neurosci Lett. 2000;289:21–4.

    Article  PubMed  CAS  Google Scholar 

  23. Seminerio MJ, Kaushal N, Shaikh J, Huber JD, Coop A, Matsumoto RR. Sigma (σ) receptor ligand, AC927 (N-phenethylpiperidine oxalate), attenuates methamphetamine-induced hyperthermia and serotonin damage in mice. Pharmacol Biochem Behav. 2011;98:12–20.

    Article  PubMed  CAS  Google Scholar 

  24. Xu YT, Kaushal N, Shaikh J, Wilson LL, Mesangeau C, McCurdy CR, Matsumoto RR. A novel substituted piperazine, CM156, attenuates the stimulant and toxic effects of cocaine in mice. J Pharmacol Exp Ther. 2010;333:491–500.

    Article  PubMed  CAS  Google Scholar 

  25. Matsumoto RR, Bowen WD, Tom MA, Vo VN, Truong DD, De Costa BR. Characterization of two novel sigma receptor ligands: antidystonic effects in rats suggest sigma receptor antagonism. Eur J Pharmacol. 1995;280:301–10.

    Article  PubMed  CAS  Google Scholar 

  26. Matsumoto RR, Shaikh J, Wilson LL, Vedam S, Coop A. Attenuation of methamphetamine-induced effects through the antagonism of sigma (σ) receptors: evidence from in vivo and in vitro studies. Eur Neuropsychopharmacol. 2008;18:871–81.

    Article  PubMed  CAS  Google Scholar 

  27. Cheng Y, Prusoff WH. Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 1973;22:3099–108.

    Article  PubMed  CAS  Google Scholar 

  28. Rodvelt KR, Oelrichs CE, Blount LR, Fan KH, Lever SZ, Lever JR, Miller DK. The sigma receptor agonist SA4503 both attenuates and enhances the effects of methamphetamine. Drug Alcohol Depend. 2011;116:203–10.

    Article  PubMed  CAS  Google Scholar 

  29. Fontanilla D, Johannessen M, Hajipour AR, Cozzi NV, Jackson MB, Ruoho AE. The hallucinogen N, N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator. Science. 2009;323:934–7.

    Article  PubMed  CAS  Google Scholar 

  30. Walker JM, Bowen WD, Patrick SL, Williams WE, Mascarella SW, Bai X, Carroll FI. A comparison of (−)-deoxybenzomorphans devoid of opiate activity with their dextrorotatory phenolic counterparts suggests role of sigma 2 receptors in motor function. Eur J Pharmacol. 1993;231:61–8.

    Article  PubMed  CAS  Google Scholar 

  31. White FJ, Kalivas PW. Neuroadaptations involved in amphetamine and cocaine addiction. Drug Alcohol Depend. 1998;51:141–53.

    Article  PubMed  CAS  Google Scholar 

  32. Graybiel AM, Besson MJ, Weber E. Neuroleptic-sensitive binding sites in the nigrostriatal system: evidence for differential distribution of sigma sites in the substantia nigra, pars compacta of the cat. J Neurosci. 1989;9:326–38.

    PubMed  CAS  Google Scholar 

  33. Ujike H, Kuroda S, Otsuki S. σ Receptor antagonists block the development of sensitization to cocaine. Eur J Pharmacol. 1996;296:123–8.

    Article  PubMed  CAS  Google Scholar 

  34. Witkin JM, Terry P, Menkel M, Hickey P, Pontecorvo M, Ferkany J, Katz JL. Effects of the selective sigma receptor ligand, 6-[6-(4-hydroxypiperidinyl)hexyloxy]-3-methylflavone (NPC 16377), on behavioral and toxic effects of cocaine. J Pharmacol Exp Ther. 1993;266:473–82.

    PubMed  CAS  Google Scholar 

  35. Takebayashi M, Hayashi T, Su TP. Nerve growth factor-induced neurite sprouting in PC12 cells involves sigma-1 receptors: implications for antidepressants. J Pharmacol Exp Ther. 2002;303:1227–37.

    Article  PubMed  CAS  Google Scholar 

  36. Hayashi T, Su TP. The potential role of sigma-1 receptors in lipid transport and lipid raft reconstitution in the brain: implication for drug abuse. Life Sci. 2005;77:1612–24.

    Article  PubMed  CAS  Google Scholar 

  37. Takebayashi M, Hayashi T, Su TP. A perspective on the new mechanism of antidepressants: neuritogenesis through sigma-1 receptors. Pharmacopsychiatry. 2004;37 Suppl 3:S208–13.

    Article  PubMed  Google Scholar 

  38. Derbez AE, Mody RM, Werling LL. σ(2)-Receptor regulation of dopamine transporter via activation of protein kinase C. J Pharmacol Exp Ther. 2002;301:306–14.

    Article  PubMed  CAS  Google Scholar 

  39. Kalivas PW, Stewart J. Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Brain Res Rev. 1991;16:223–44.

    Article  PubMed  CAS  Google Scholar 

  40. Yang S, Alkayed NJ, Hurn PD, Kirsch JR. Cyclic adenosine monophosphate response element-binding protein phosphorylation and neuroprotection by 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP). Anesth Analg. 2009;108:964–70.

    Article  PubMed  CAS  Google Scholar 

  41. McDaid J, Graham MP, Napier TC. Methamphetamine-induced sensitization differentially alters pCREB and ΔFosB throughout the limbic circuit of the mammalian brain. Mol Pharmacol. 2006;70:2064–74.

    Article  PubMed  CAS  Google Scholar 

  42. Largent BL, Gundlach AL, Snyder SH. Psychotomimetic opiate receptors labeled and visualized with (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine. Proc Natl Acad Sci U S A. 1984;81:4983–7.

    Article  PubMed  CAS  Google Scholar 

  43. Takahashi S, Horikomi K, Kato T. MS-377, a novel selective sigma(1) receptor ligand, reverses phencyclidine-induced release of dopamine and serotonin in rat brain. Eur J Pharmacol. 2001;427:211–9.

    Article  PubMed  CAS  Google Scholar 

  44. Gundlach AL, Largent BL, Snyder SH. Autoradiographic localization of sigma receptor binding sites in guinea pig and rat central nervous system with (+)3H-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine. J Neurosci. 1986;6:1757–70.

    PubMed  CAS  Google Scholar 

  45. Tam SW. Naloxone-inaccessible sigma receptor in rat central nervous system. Proc Natl Acad Sci U S A. 1983;80:6703–7.

    Article  PubMed  CAS  Google Scholar 

  46. Chen JC, Chen PC, Chiang YC. Molecular mechanisms of psychostimulant addiction. Chang Gung Med J. 2009;32:148–54.

    PubMed  Google Scholar 

  47. Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, Cadoni C, Acquas E, Carboni E, Valentini V, Lecca D. Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology. 2004;47 Suppl 1:227–41.

    Article  PubMed  Google Scholar 

  48. Thompson TL, Bridges S, Miller C. Modulation of dopamine uptake in rat nucleus accumbens: effect of specific dopamine receptor antagonists and sigma ligands. Neurosci Lett. 2001;312:169–72.

    Article  PubMed  CAS  Google Scholar 

  49. Ault DT, Werling LL. Phencyclidine and dizocilpine modulate dopamine release from rat nucleus accumbens via sigma receptors. Eur J Pharmacol. 1999;386:145–53.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the National Institute on Drug Abuse (DA013978 and DA023205).

Author information

Authors and Affiliations

  1. Department Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, P.O. Box 9500, Morgantown, West Virginia, 26506, USA

    Michael J. Seminerio, Matthew J. Robson & Rae R. Matsumoto

  2. Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, Mississippi, 38677, USA

    Ahmed H. Abdelazeem, Christophe Mesangeau & Christopher R. McCurdy

  3. Department of Pharmaceutics, School of Pharmacy, University of Mississippi, University, Mississippi, 38677, USA

    Seshulatha Jamalapuram & Bonnie A. Avery

Authors
  1. Michael J. Seminerio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthew J. Robson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ahmed H. Abdelazeem
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christophe Mesangeau
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seshulatha Jamalapuram
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bonnie A. Avery
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christopher R. McCurdy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rae R. Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rae R. Matsumoto.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Seminerio, M.J., Robson, M.J., Abdelazeem, A.H. et al. Synthesis and Pharmacological Characterization of a Novel Sigma Receptor Ligand with Improved Metabolic Stability and Antagonistic Effects Against Methamphetamine. AAPS J 14, 43–51 (2012). https://doi.org/10.1208/s12248-011-9311-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12248-011-9311-8

Key words

Search

Navigation