Skip to main content
SpringerLink
Log in

Analogs of the κ opioid receptor antagonist arodyn cyclized by ring-closing metathesis retain κ opioid receptor affinity, selectivity and κ opioid receptor antagonism

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

Abstract

The dynorphin (Dyn) A analog arodyn (Ac[Phe1-3,Arg4,d-Ala8]Dyn A-(1–11)NH2) is a κ opioid receptor-selective antagonist, but as a linear peptide it is conformationally flexible and subject to metabolism by proteases. To restrict its conformational flexibility both short- and long-range cyclizations via ring-closing metathesis (RCM) involving residues in both the N-terminal “message” and C-terminal “address” sequences were explored. Cyclization between allyglycine (AllGly) residues in positions 5 and 8 yielded peptides with the highest κ opioid receptor affinity (Ki = 54 and 63 nM) and selectivity for κ over µ receptors (185- and 149-fold) comparable to arodyn (175-fold), with similar results for the peptides with the cis and trans double bond configurations; both isomers exhibited competitive antagonism of κ opioid receptors with potencies similar to arodyn. The minor cis isomer cyclized between AllGly residues in positions 2 and 8 exhibited similar κ receptor affinity to arodyn, but lacked selectivity for κ over µ opioid receptors. These results provide important structure-activity relationship information for cyclization of arodyn that we are using in the design of the next generation of cyclic arodyn analogs.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Scheme 1

Similar content being viewed by others

Notes

  1. Unless otherwise indicated, all amino acids are the L-isomer, and standard abbreviations are used according to the IUPAC-IUB Joint Commission of Biochemical Nomenclature [27]

References

  1. Aldrich JV, McLaughlin JP. Peptide kappa opioid receptor ligands: potential for drug development. AAPS J. 2009;11:312–22. https://doi.org/10.1208/s12248-009-9105-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Carroll FI, Carlezon WA Jr. Development of kappa opioid receptor antagonists. J Med Chem. 2013;56:2178–95. https://doi.org/10.1021/jm301783x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Urbano M, Guerrero M, Rosen H, Roberts E. Antagonists of the kappa opioid receptor. Bioorg Med Chem Lett. 2014;24:2021–32. https://doi.org/10.1016/j.bmcl.2014.03.040

    Article  CAS  PubMed  Google Scholar 

  4. Carlezon WA Jr, Krystal AD. Kappa-opioid antagonists for psychiatric disorders: from bench to clinical trials. Depress Anxiety. 2016;33:895–906. https://doi.org/10.1002/da.22500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Helal MA, Habib ES, Chittiboyina AG. Selective kappa opioid antagonists for treatment of addiction, are we there yet? Eur J Med Chem. 2017;141:632–47. https://doi.org/10.1016/j.ejmech.2017.10.012

    Article  CAS  PubMed  Google Scholar 

  6. Metcalf MD, Coop A. Kappa opioid antagonists: past successes and future prospects. AAPS J. 2005;7:E704–22. https://doi.org/10.1208/aapsj070371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Guerrero M, Urbano M, Kim EK, Gamo AM, Riley S, Abgaryan L, et al. Design and synthesis of a novel and selective kappa opioid receptor (KOR) antagonist (BTRX-335140). J Med Chem. 2019;62:1761–80. https://doi.org/10.1021/acs.jmedchem.8b01679

  8. Bennett MA, Murray TF, Aldrich JV. Identification of arodyn, a novel acetylated dynorphin A-(1-11) analogue, as a κ opioid receptor antagonist. J Med Chem. 2002;45:5617–9. https://doi.org/10.1021/jm025575g

    Article  CAS  PubMed  Google Scholar 

  9. Carey AN, Borozny K, Aldrich JV, McLaughlin JP. Reinstatement of cocaine place-conditioning prevented by the peptide kappa-opioid receptor antagonist arodyn. Eur J Pharmacol. 2007;569:84–9. https://doi.org/10.1016/j.ejphar.2007.05.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Aldrich JV, Patkar KA, McLaughlin JP. Zyklophin, a systemically active selective kappa opioid receptor peptide antagonist with short duration of action. Proc Natl Acad Sci USA. 2009;106:18396–401. https://doi.org/10.1073/pnas.0910180106

    Article  PubMed  PubMed Central  Google Scholar 

  11. Fang WJ, Murray TF, Aldrich JV. Design, synthesis, and opioid activity of arodyn analogs cyclized by ring-closing metathesis involving Tyr(allyl). Bioorg Med Chem. 2018;26:1157–61. https://doi.org/10.1016/j.bmc.2017.11.029

    Article  CAS  PubMed  Google Scholar 

  12. Gisemba SA, Ferracane MJ, Murray TF, Aldrich JV. Conformational constraint between aromatic residue side chains in the “message” sequence of the peptide arodyn using ring closing metathesis results in a potent and selective kappa opioid receptor antagonist. J Med Chem. 2021;64:3153–64. https://doi.org/10.1021/acs.jmedchem.0c01984

  13. Fu GC, Grubbs RH. The application of catalytic ring-closing olefin metathesis to the synthesis of unsaturated oxygen heterocycles. J Am Chem Soc. 1992;114:5426–7. https://doi.org/10.1021/ja00039a065

    Article  CAS  Google Scholar 

  14. Miller SJ, Blackwell HE, Grubbs RH. Application of ring-closing metathesis to the synthesis of rigidified amino acids and peptides. J Am Chem Soc. 1996;118:9606–14. https://doi.org/10.1021/ja961626l

    Article  CAS  Google Scholar 

  15. Stymiest JL, Mitchell BF, Wong S, Vederas JC. Synthesis of oxytocin analogues with replacement of sulfur by carbon gives potent antagonists with increased stability. J Org Chem. 2005;70:7799–809. https://doi.org/10.1021/jo050539l

    Article  CAS  PubMed  Google Scholar 

  16. Reichwein JF, Versluis C, Liskamp RMJ. Synthesis of cyclic peptides by ring-closing metathesis. J Org Chem. 2000;65:6187–95. https://doi.org/10.1021/jo000759t

    Article  CAS  PubMed  Google Scholar 

  17. Nutt RF, Veber DF, Saperstein R. Synthesis of nonreducible bicyclic analogs of somatostatin. J Am Chem Soc. 1980;102:6539–45. https://doi.org/10.1021/ja00541a025

    Article  CAS  Google Scholar 

  18. Vig BS, Murray TF, Aldrich JV. Synthesis of novel basic head-to-side chain cyclic dynorphin A analogs: strategies and side reactions. Biopolymers. 2003;71:620–37. https://doi.org/10.1002/bip.10591

    Article  CAS  PubMed  Google Scholar 

  19. Berezowska I, Chung NN, Lemieux C, Wilkes BC, Schiller PW. Cyclic dermorphin tetrapeptide analogues obtained via ring-closing metathesis. Acta Biochim Pol. 2006;53:73–6.

    Article  CAS  Google Scholar 

  20. Berezowska I, Chung NN, Lemieux C, Wilkes BC, Schiller PW. Dicarba analogues of the cyclic enkephalin peptides H-Tyr-c[D-Cys-Gly-Phe-D(or L)-Cys]NH2 retain high opioid activity. J Med Chem.2007;50:1414–7. https://doi.org/10.1021/jm061294n

  21. Mollica A, Guardiani G, Davis P, Ma SW, Porreca F, Lai J. et al.Synthesis of stable and potent δ/μ opioid peptides: analogues of H-Tyr-c[D-Cys-Gly-Phe-D-Cys]-OH by ring-closing metathesis.J Med Chem. 2007;50:3138–42. https://doi.org/10.1021/jm061048b

  22. Berezowska I, Lemieux C, Chung NN, Wilkes BC, Schiller PW. Cyclic opioid peptide agonists and antagonists obtained via ring-closing metathesis. Chem Biol Drug Des. 2009;74:329–34. https://doi.org/10.1111/j.1747-0285.2009.00867.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Stefanucci A, Lei W, Pieretti S, Dimmito MP, Luisi G, Novellino E, et al. Novel cyclic biphalin analogues by ruthenium-catalyzed ring closing metathesis: in vivo and in vitro biological profile. ACS Med Chem Lett. 2019;10:450–6. https://doi.org/10.1021/acsmedchemlett.8b00495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fang WJ, Cui Y, Murray TF, Aldrich JV. Design, synthesis, and pharmacological activities of dynorphin A analogues cyclized by ring-closing metathesis. J Med Chem. 2009;52:5619–25. https://doi.org/10.1021/jm900577k

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gisemba SA, Aldrich JV. Optimized ring closing metathesis reaction conditions to suppress desallyl side products in the solid-phase synthesis of cyclic peptides involving tyrosine(O-allyl). J Org Chem. 2020;85:1407–15. https://doi.org/10.1021/acs.joc.9b02345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bennett MA, Murray TF, Aldrich JV. Structure-activity relationships of arodyn, a novel acetylated kappa opioid receptor antagonist. J Pept Res. 2005;65:322–32. https://doi.org/10.1111/j.1399-3011.2005.00216.x

    Article  CAS  PubMed  Google Scholar 

  27. Cornishbowen A. Nomenclature and symbolism for amino acids and peptides: recommendations 1983. Eur J Biochem. 1984;138:9–37. https://doi.org/10.1111/j.1432-1033.1984.tb07877.x

    Article  Google Scholar 

  28. Fang WJ, Bennett MA, Aldrich JV. Deletion of Ac-NMePhe1 from [NMePhe1]arodyn under acidic conditions: 1. Effects of cleavage conditions and N-terminal functionality. Biopolymers. 2011;96:97–102. https://doi.org/10.1002/bip.21496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bovey FA, Mirau PA, Gutowsky HS. Nuclear Magnetic Resonance Spectroscopy. 2nd ed. (Academic Press, San Diego, 1988). https://doi.org/10.1002/pol.1990.140280106.

  30. Braun S, Kalinowski HO, Berger S. 150 and More Basic NMR Experiments. 2nd ed. (Wiley-VCH, Weinheim, 1998).

  31. Silverstein RM, Webster FX. Spectrometric Identification of Organic Compounds. (John Wiley & Sons, Inc., New York, 1997).

  32. Arttamangkul S, Ishmael JE, Murray TF, Grandy DK, DeLander GE, Kieffer BL, et al. Synthesis and opioid activity of conformationally constrained dynorphin A analogues. 2. Conformational constraint in the “address” sequence. J Med Chem. 1997;40:1211–8. https://doi.org/10.1021/jm960753p

    Article  CAS  PubMed  Google Scholar 

  33. Fang WJ, Bennett MA, Murray TF, Aldrich JV. Deletion of Ac-NMePhe1 from [NMePhe1]arodyn under acidic conditions: 2. Effects of substitutions on pharmacological activity. Biopolymers. 2011;96:103–10. https://doi.org/10.1002/bip.21495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kaiser E, Colescott RL, Bossinger CD, Cook PI. Color test for detection of free terminal amino groups in the solid-phase synthesis of peptides. Anal Biochem. 1970;34:595–8. https://doi.org/10.1016/0003-2697(70)90146-6

    Article  CAS  PubMed  Google Scholar 

  35. Solé NA, Barany G. Optimization of solid-phase synthesis of [Ala8]-dynorphin A. J Org Chem. 1992;57:5399–403. https://doi.org/10.1021/jo00046a022

    Article  Google Scholar 

  36. Cheng YC, Prusoff WH. Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 percent inhibition (IC50) of an enzymatic reaction. Biochem Pharmacol. 1973;22:3099–108. https://doi.org/10.1016/0006-2952(73)90196-2

    Article  CAS  PubMed  Google Scholar 

  37. Ross NC, Reilley KJ, Murray TF, Aldrich JV, McLaughlin JP. Novel opioid cyclic tetrapeptides: Trp isomers of CJ-15,208 exhibit distinct opioid receptor agonism and short-acting kappa opioid receptor antagonism. Br J Pharmacol. 2012;165:1097–108. https://doi.org/10.1111/j.1476-5381.2011.01544.x

    Article  PubMed  PubMed Central  Google Scholar 

  38. Schild HO. pA, a new scale for the measurement of drug antagonism. Br J Pharmacol Chemother. 1947;2:189–206. https://doi.org/10.1111/j.1476-5381.1947.tb00336.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research was supported by the National Institute on Drug Abuse grant R01 DA018832. We thank Ms. Bridget Sefranek for her excellent technical assistance with the radioligand and [35S]GTPγS binding assays.

Author information

Author notes

  1. Wei-Jie Fang

    Present address: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zheijang, China

Authors and Affiliations

  1. Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, 66045, USA

    Wei-Jie Fang & Jane V. Aldrich

  2. Department of Pharmacology, Creighton University, Omaha, NE, 68178, USA

    Thomas F. Murray

  3. Department of Medicinal Chemistry, University of Florida, Gainesville, FL, 32610, USA

    Jane V. Aldrich

Authors
  1. Wei-Jie Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas F. Murray
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jane V. Aldrich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Wei-Jie Fang, Thomas F. Murray or Jane V. Aldrich.

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.

This paper is dedicated to Dr. Gary Gunewald, an outstanding chemist who has contributed so much to the field of medicinal chemistry and a wonderful colleague.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fang, WJ., Murray, T.F. & Aldrich, J.V. Analogs of the κ opioid receptor antagonist arodyn cyclized by ring-closing metathesis retain κ opioid receptor affinity, selectivity and κ opioid receptor antagonism. Med Chem Res 30, 1397–1407 (2021). https://doi.org/10.1007/s00044-021-02758-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-021-02758-x

Keywords

Search

Navigation