Display options
Cite
Liu S, Zha C, Nacro K, et al. Design and synthesis of 4-heteroaryl 1,2,3,4-tetrahydroisoquinolines as triple reuptake inhibitors. ACS Med Chem Lett. 2014;5(7):760-5doi: 10.1021/ml500053b.
Liu, S., Zha, C., Nacro, K., Hu, M., Cui, W., Yang, Y. L., Bhatt, U., Sambandam, A., Isherwood, M., Yet, L., Herr, M. T., Ebeltoft, S., Hassler, C., Fleming, L., Pechulis, A. D., Payen-Fornicola, A., Holman, N., Milanowski, D., Cotterill, I., Mozhaev, V., Khmelnitsky, Y., Guzzo, P. R., Sargent, B. J., Molino, B. F., Olson, R., King, D., Lelas, S., Li, Y. W., Johnson, K., Molski, T., Orie, A., Ng, A., Haskell, R., Clarke, W., Bertekap, R., O'Connell, J., Lodge, N., Sinz, M., Adams, S., Zaczek, R., & Macor, J. E. (2014). Design and synthesis of 4-heteroaryl 1,2,3,4-tetrahydroisoquinolines as triple reuptake inhibitors. ACS medicinal chemistry letters, 5(7), 760-5. https://doi.org/10.1021/ml500053b
Liu, Shuang, et al. "Design and synthesis of 4-heteroaryl 1,2,3,4-tetrahydroisoquinolines as triple reuptake inhibitors." ACS medicinal chemistry letters vol. 5,7 (2014): 760-5. doi: https://doi.org/10.1021/ml500053b
Liu S, Zha C, Nacro K, Hu M, Cui W, Yang YL, Bhatt U, Sambandam A, Isherwood M, Yet L, Herr MT, Ebeltoft S, Hassler C, Fleming L, Pechulis AD, Payen-Fornicola A, Holman N, Milanowski D, Cotterill I, Mozhaev V, Khmelnitsky Y, Guzzo PR, Sargent BJ, Molino BF, Olson R, King D, Lelas S, Li YW, Johnson K, Molski T, Orie A, Ng A, Haskell R, Clarke W, Bertekap R, O'Connell J, Lodge N, Sinz M, Adams S, Zaczek R, Macor JE. Design and synthesis of 4-heteroaryl 1,2,3,4-tetrahydroisoquinolines as triple reuptake inhibitors. ACS Med Chem Lett. 2014 May 13;5(7):760-5. doi: 10.1021/ml500053b. eCollection 2014 Jul 10. PMID: 25050161; PMCID: PMC4094255.
Copy Download .nbib Format: NLM
Share it on

ACS Med Chem Lett. 2014 May 13;5(7):760-5. doi: 10.1021/ml500053b. eCollection 2014 Jul 10.

Design and synthesis of 4-heteroaryl 1,2,3,4-tetrahydroisoquinolines as triple reuptake inhibitors.

ACS medicinal chemistry letters

Shuang Liu, Congxiang Zha, Kassoum Nacro, Min Hu, Wenge Cui, Yuh-Lin Yang, Ulhas Bhatt, Aruna Sambandam, Matthew Isherwood, Larry Yet, Michael T Herr, Sarah Ebeltoft, Carla Hassler, Linda Fleming, Anthony D Pechulis, Anne Payen-Fornicola, Nicholas Holman, Dennis Milanowski, Ian Cotterill, Vadim Mozhaev, Yuri Khmelnitsky, Peter R Guzzo, Bruce J Sargent, Bruce F Molino, Richard Olson, Dalton King, Snjezana Lelas, Yu-Wen Li, Kim Johnson, Thaddeus Molski, Anitra Orie, Alicia Ng, Roy Haskell, Wendy Clarke, Robert Bertekap, Jonathan O'Connell, Nicholas Lodge, Michael Sinz, Stephen Adams, Robert Zaczek, John E Macor

Affiliations

  1. AMRI , 26 Corporate Circle, Albany, New York 12212, United States.
  2. Bristol Myers Squibb R&D , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.

PMID: 25050161 PMCID: PMC4094255 DOI: 10.1021/ml500053b

Abstract

A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure-activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound 10i (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forced-swim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/kg (po), respectively. At efficacious doses in these assays, 10i exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of 10i revealed the formation of a significant active metabolite, compound 13.

Keywords: TRI; Triple reuptake inhibitor; antidepressant; depression; dopamine reuptake inhibitor; norepinephrine reuptake inhibitor; serotonin reuptake inhibitor

References

  1. Neuropharmacology. 2008 Jul;55(1):63-70 - PubMed
  2. J Med Chem. 2010 Mar 25;53(6):2534-51 - PubMed
  3. J Med Chem. 2011 Apr 28;54(8):2924-32 - PubMed
  4. J Med Chem. 2011 Aug 11;54(15):5283-95 - PubMed
  5. Neuropsychopharmacology. 2002 Nov;27(5):699-711 - PubMed
  6. J Clin Psychiatry. 2003 Dec;64(12):1465-75 - PubMed
  7. Bioorg Med Chem Lett. 2012 Dec 1;22(23):7219-22 - PubMed
  8. Chem Res Toxicol. 2009 Feb;22(2):267-79 - PubMed
  9. Depress Anxiety. 1998;7(2):89-91 - PubMed
  10. J Pharmacol Exp Ther. 2000 Oct;295(1):51-7 - PubMed
  11. Am J Geriatr Psychiatry. 2006 Feb;14(2):181-5 - PubMed
  12. J Pharmacol Exp Ther. 2008 Nov;327(2):573-83 - PubMed
  13. Prim Care Companion J Clin Psychiatry. 2005;7(3):106-13 - PubMed
  14. Bioorg Med Chem Lett. 2010 Sep 15;20(18):5559-66 - PubMed
  15. Arch Gen Psychiatry. 2005 Jun;62(6):617-27 - PubMed
  16. Am J Psychiatry. 2004 May;161(5):826-35 - PubMed
  17. N Engl J Med. 2006 Mar 23;354(12):1243-52 - PubMed
  18. Depress Anxiety. 2006;23(3):178-81 - PubMed
  19. Eur J Pharmacol. 2000 Sep 29;405(1-3):365-73 - PubMed
  20. Int J Neuropsychopharmacol. 2012 Sep;15(8):1167-72 - PubMed
  21. Expert Rev Neurother. 2005 May;5(3):325-31 - PubMed
  22. Eur J Pharmacol. 2003 Feb 14;461(2-3):99-104 - PubMed

Publication Types