Skip to main content

Advertisement

SpringerLink
Log in

Design, synthesis, and evaluation of functionalized 5-(4-arylpiperazin-1-yl)-N-arylpentanamides as selective dopamine D3 receptor ligands

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

Substance use disorder remains a major, unmet medical need. Cocaine is one of the most commonly abused recreational drugs and in 2018, there were over 5.5 million cocaine users. There are no approved therapies for the treatment of cocaine use disorder, but the D3 dopamine receptor has been identified as a potential therapeutic target. Our initial lead compound (6) is a potent D3 ligand with a high level of selectivity for D3 over D2, but its solubility is low. We have identified a new series of functionalized 5-(4-arylpiperazin-1-yl)-N-arylpentanamides (7) that are potent D3 binders that have moderate to high selectivity for D3 over D2. Exemplary members of this series were also significantly more soluble than our initial lead compound (6).

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
Scheme 1
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Bose J, Hedden SL, Lipari RN, Park-Lee E. Key substance use and mental health indicators in the United States: Results from the 2017 National Survey on Drug Use and Health, HHS Publication No. SMA 18-5068, NSDUH Series H-53, Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration, https://www.samhsa.gov/data/

  2. NIDA report Health Consequences of Drug Misuse. 2019. https://www.drugabuse.gov/related-topics/health-consequences-drug-misuse

  3. Balk JH. Dopamine signaling in reward-related behaviors. Front Neural Circuits. 2013;7:1–16. https://doi.org/10.3389/fncir.2013.00152

    Article  CAS  Google Scholar 

  4. Wise RA, Koob GF. The development and maintenance of drug addiction. Neuropsychopharmacology. 2014;39:254–62. https://doi.org/10.1038/npp.2013.261

    Article  PubMed  Google Scholar 

  5. Alonso-Matias L, Reyes-Zamorano E, Gonzalez-Olvera JJ. Cognitive functions of subjects with cocaine and crack dependency disorder during early abstinence. Rev Neurol 2019;68:271–80. https://doi.org/10.33588/rn.6807.2018119

    Article  PubMed  CAS  Google Scholar 

  6. Substance Abuse and Mental Health Services Administration, Drug Abuse Warning Network. National Estimates of Drug-Related Emergency Department Visits. HHS Publication No. (SMA) 13-4760, DAWN Series D-39. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2011. https://www.samhsa.gov/data/sites/default/files/DAWN2k11ED/DAWN2k11ED/DAWN2k11ED.pdf

  7. Schierenberg A, van Amsterdam J, van den Brink W, Goudriaan AE. Efficacy of contingency management for cocaine dependence treatment: a review of the evidence. Curr Drug Abus Rev. 2012;5:320–31. https://doi.org/10.2174/1874473711205040006

    Article  CAS  Google Scholar 

  8. Penberthy JK, Ait-Daoud N, Vaughan M, Fanning T. Review of treatment for cocaine dependence. Curr Drug Abus Rev. 2010;3:49–62. https://doi.org/10.2174/1874473711003010049

    Article  CAS  Google Scholar 

  9. Oliveto A, Poling J, Mancino MJ, Feldman Z, Cubells JF, Pruzinsky R, et al. Randomized, double-blind, placebo-controlled trial of disulfiram for the treatment of cocaine dependence in methadone-stabilized patients. Drug Alcohol Depend. 2011;113:184–91. https://doi.org/10.1016/j.drugalcdep.2010.07.022

    Article  PubMed  CAS  Google Scholar 

  10. McCance-Katz EF, Kosten TR, Jatlow P. Disulfiram effects on acute cocaine administration. Drug Alcohol Depend. 1998;52:27–39. https://doi.org/10.1016/s0376-8716(98)00050-7

    Article  PubMed  CAS  Google Scholar 

  11. Johnson BA, Ait-Daoud N, Wang XQ, Penberthy JK, Javors MA, Seneviratne C, et al. Topiramate for the treatment of cocaine addiction: a randomized clinical trial. JAMA Psychiatry. 2013;70:338–1346. https://doi.org/10.1001/jamapsychiatry.2013.2295

    Article  CAS  Google Scholar 

  12. Somoza EC, Winship D, Gorodetzky CW, Lewis D, Ciraulo DA, Galloway GP, et al. A multisite, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of vigabatrin for treating cocaine dependence. JAMA Psychiatry. 2013;70:630–7. https://doi.org/10.1001/jamapsychiatry.2013.872

    Article  PubMed  CAS  Google Scholar 

  13. Prince V, Bowling KC. Topiramate in the treatment of cocaine use disorder. Am J Health Sys Pharm. 2018;75:e13–22. https://doi.org/10.2146/ajhp160542

    Article  Google Scholar 

  14. Placenza FM, Fletcher PJ, Vaccarino FJ, Erb S. Effects of central neurokinin-1 receptor antagonism on cocaine- and opiate-induced locomotor activity and self-administration behaviour in rats. Pharmacol Biochem Behav. 2006;84:94–101. https://doi.org/10.1016/j.pbb.2006.04.011

    Article  PubMed  CAS  Google Scholar 

  15. Baker DA, McFarland K, Lake RW, Shen H, Toda S, Kalivas PW. N‐Acetyl cysteine‐induced blockade of cocaine‐induced reinstatement. Ann N. Y Acad Sci. 2003;1003:349–51. https://doi.org/10.1196/annals.1300.023

    Article  PubMed  Google Scholar 

  16. Harvey-Lewis C, Li Z, Higgins GA, Fletcher PJ. The 5-HT2C receptor agonist lorcaserin reduces cocaine self-administration, reinstatement of cocaine-seeking and cocaine induced locomotor activity. Neuropharmacology. 2016;101:237–45. https://doi.org/10.1016/j.neuropharm.2015.09.028

    Article  PubMed  CAS  Google Scholar 

  17. Roeper J. Dissecting the diversity of midbrain dopamine neurons. Trends Neurosci. 2013;36:336–42. https://doi.org/10.1016/j.tins.2013.03.003

    Article  PubMed  CAS  Google Scholar 

  18. Jaber M, Robinson SW, Missale C, Caron MG. Dopamine receptors and brain function. Neuropharmacology. 1996;35:1503–19. https://doi.org/10.1016/s0028-3908(96)00100-1

    Article  PubMed  CAS  Google Scholar 

  19. Staley JK, Mash DC. Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities. J Neurosci. 1996;16:6100–6. https://doi.org/10.1523/JNEUROSCI.16-19-06100.1996

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Segal DM, Moraes CT, Mash DC. Up-regulation of D3 dopamine receptor mRNA in the nucleus accumbens of human cocaine fatalities. Brain Res Mol Brain Res. 1997;45:335–9. https://doi.org/10.1016/s0169-328x(97)00025-9

    Article  PubMed  CAS  Google Scholar 

  21. Mash DC, Staley JK. D3 dopamine and kappa opioid receptor alterations in human brain of cocaine-overdose victims. Ann N. Y Acad Sci. 1999;877:507–22. https://doi.org/10.1111/j.1749-6632.1999.tb09286.x

    Article  PubMed  CAS  Google Scholar 

  22. Keck TM, John WS, Czoty PW, Nader MA, Newman AH. Identifying medication targets for psychostimulant addiction: unraveling the dopamine D3 receptor hypothesis. J Med Chem. 2015;58:5361–80. https://doi.org/10.1021/jm501512b

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Newman AH, Blaylock BL, Nader MA, Bergman J, Sibley DR, Skolnick P. Medication discovery for addiction: translating the dopamine D3 receptor hypothesis. Biochem Pharm. 2012;84:882–90. https://doi.org/10.1016/j.bcp.2012.06.023

    Article  PubMed  CAS  Google Scholar 

  24. Payer D, Balasubramaniam G, Boileau I. What is the role of the D3 receptor in addiction? A mini review of PET studies with [11C]-(+)-PHNO. Prog Neuropsychopharmacol Biol Psychiatry. 2014;52:4–8. https://doi.org/10.1016/j.pnpbp.2013.08.012

    Article  PubMed  CAS  Google Scholar 

  25. Blaylock BL, Nader MA. Dopamine D3 receptor function and cocaine exposure. Neuropsychopharmacology. 2012;37:297–8. https://doi.org/10.1038/npp.2011.170

    Article  PubMed  Google Scholar 

  26. Millan MJ, Loiseau F, Dekeyne A, Gobert A, Flik G, Cremers TI, et al. S33138 (N-[4-[2-[(3aS, 9bR)-8-cyano-1, 3a, 4, 9b-tetrahydro [1] benzopyrano [3, 4-c] pyrrol-2 (3H)-yl)-ethyl] phenyl-acetamide), a preferential dopamine D3 versus D2 receptor antagonist and potential antipsychotic agent: III. Actions in models of therapeutic activity and induction of side effects. J Pharmacol Exp Ther. 2008;324:1212–26.

    Article  CAS  Google Scholar 

  27. Chen PJ, Taylor M, Griffin SA, Amani A, Hayatshahi H, Korzekwa K, et al. Design, synthesis, and evaluation of N-(4-(4-phenyl piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamides as selective dopamine D3 receptor ligands. Bioorg Med Chem Lett. 2019;29:2690–4. https://doi.org/10.1016/j.bmcl.2019.07.020

    Article  PubMed  CAS  Google Scholar 

  28. Hayatshahi HS, Xu K, Griffin SA, Taylor M, Mach RH, Liu J, et al. Analogues of arylamide phenylpiperazine ligands to investigate the factors influencing D3 dopamine receptor bitropic binding and receptor subtype selectivity. ACS Chem Neurosci. 2018;9:2972–83. https://doi.org/10.1021/acschemneuro.8b00142

    Article  PubMed  CAS  Google Scholar 

  29. Kilford PJ, Stringer R, Sohal B, Houston JB, Galetin A. Prediction of drug clearance by glucuronidation from in vitro data: use of combined cytochrome P450 and UDP-glucuronosyltransferase cofactors in alamethicin-activated human liver microsomes. Drug Metab Dispos. 2009;37:82–9.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The research reported in this publication was supported by the National Institute on Drug Abuse (NIDA)/National Institutes of Health (NIH) under award numbers DA029840-06A1 and DA023957.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA, 194140, USA

    Benjamin E. Blass, Peng-Jen Chen & John C. Gordon

  2. Department of Pharmacology and Neuroscience, Center, University of North Texas Health Science, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA

    Michelle Taylor, Suzy A. Griffin & Robert R. Luedtke

Authors
  1. Benjamin E. Blass
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peng-Jen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michelle Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Suzy A. Griffin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John C. Gordon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert R. Luedtke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Benjamin E. Blass.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Blass, B.E., Chen, PJ., Taylor, M. et al. Design, synthesis, and evaluation of functionalized 5-(4-arylpiperazin-1-yl)-N-arylpentanamides as selective dopamine D3 receptor ligands. Med Chem Res 31, 132–145 (2022). https://doi.org/10.1007/s00044-021-02825-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-021-02825-3

Keywords

Search

Navigation