Synthesis and evaluation of 4-substituted piperidines and piperazines as balanced affinity μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands

doi:10.1016/j.bmcl.2013.12.021

. 2014 Jan 15;24(2):548-51.

doi: 10.1016/j.bmcl.2013.12.021. Epub 2013 Dec 11.

Synthesis and evaluation of 4-substituted piperidines and piperazines as balanced affinity μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands

Aaron M Bender¹, Mary J Clark², Michael P Agius¹, John R Traynor², Henry I Mosberg³

Affiliations

¹ Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States; Interdepartmental Program in Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, United States.
² Department of Pharmacology, Medical School, University of Michigan, Ann Arbor, MI 48109, United States.
³ Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States; Interdepartmental Program in Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, United States. Electronic address: him@med.umich.edu.

PMID: 24365161
PMCID: PMC3919453
DOI: 10.1016/j.bmcl.2013.12.021

Synthesis and evaluation of 4-substituted piperidines and piperazines as balanced affinity μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands

Aaron M Bender et al. Bioorg Med Chem Lett. 2014.

. 2014 Jan 15;24(2):548-51.

doi: 10.1016/j.bmcl.2013.12.021. Epub 2013 Dec 11.

Authors

Aaron M Bender¹, Mary J Clark², Michael P Agius¹, John R Traynor², Henry I Mosberg³

Affiliations

¹ Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States; Interdepartmental Program in Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, United States.
² Department of Pharmacology, Medical School, University of Michigan, Ann Arbor, MI 48109, United States.
³ Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States; Interdepartmental Program in Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, United States. Electronic address: him@med.umich.edu.

PMID: 24365161
PMCID: PMC3919453
DOI: 10.1016/j.bmcl.2013.12.021

Abstract

In this letter, we describe a series of 4-substituted piperidine and piperazine compounds based on tetrahydroquinoline 1, a compound that shows balanced, low nanomolar binding affinity for the mu opioid receptor (MOR) and the delta opioid receptor (DOR). We have shown that by changing the length and flexibility profile of the side chain in this position, binding affinity is improved at both receptors by a significant degree. Furthermore, several of the compounds described herein display good efficacy at MOR, while simultaneously displaying DOR antagonism. The MOR agonist/DOR antagonist has shown promise in the reduction of negative side effects displayed by selective MOR agonists, namely the development of dependence and tolerance.

Keywords: Mixed function opioids; Opioid peptidomimetics.

PubMed Disclaimer

Figures

**Scheme 1. Synthesis of compound 2a**
a. Reagents and conditions: (a) triphenylphosphinebenzyl bromide, n-BuLi, THF, reflux; (b) H₂, 10% Pd/C, MeOH, 50 psi; (c) TFA, DCM; (d) Boc-L-Dmt, HATU, HOBt-Cl, DIEA, DMF, 4Å molecular sieves, 40°C; (e) TFA, DCM.

**Scheme 2. Synthesis of analogues 3–5, 8, 9, 12a**
a. Reagents and conditions: (a) Boc-L-Dmt, PyBOP or HATU, HOBt-Cl, DIEA, DMF; (b) TFA, DCM; (c) MsCl, Et₃N, DCM, 0°C; (d) piperazine, THF, reflux.

**Scheme 3. Synthesis of analogues 6, 7, 10, 11a**
a. Reagents and conditions: (a) O=P(CH₃CH₂O)₂CH₂CO₂CH₃, NaH, THF, 0°C; (b) O=P(CF₃CH₂O)₂CH₂CO₂CH₃, NaH, THF, 0°C; (c) DIBAL, DCM, −78°C; (d) H₂, 10% Pd/C, MeOH, 15 psi; (e) LAH, THF, 0°C; (f) MsCl, Et₃N, DCM, 0°C; (g) piperazine, THF, reflux.

See this image and copyright information in PMC

Cited by

The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of "Tail Wags Dog" Experiments.
Wang M, Irvin TC, Herdman CA, Hanna RD, Hassan SA, Lee YS, Kaska S, Crowley RS, Prisinzano TE, Withey SL, Paronis CA, Bergman J, Inan S, Geller EB, Adler MW, Kopajtic TA, Katz JL, Chadderdon AM, Traynor JR, Jacobson AE, Rice KC. Wang M, et al. Molecules. 2020 Jun 6;25(11):2640. doi: 10.3390/molecules25112640. Molecules. 2020. PMID: 32517185 Free PMC article.
Tryptophan Substitution in CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) Introduces δ-Opioid Receptor Antagonism, Preventing Antinociceptive Tolerance and Stress-Induced Reinstatement of Extinguished Cocaine-Conditioned Place Preference.
Scherrer KH, Eans SO, Medina JM, Senadheera SN, Khaliq T, Murray TF, McLaughlin JP, Aldrich JV. Scherrer KH, et al. Pharmaceuticals (Basel). 2023 Aug 29;16(9):1218. doi: 10.3390/ph16091218. Pharmaceuticals (Basel). 2023. PMID: 37765026 Free PMC article.
Rapid Synthesis of Boc-2',6'-dimethyl-l-tyrosine and Derivatives and Incorporation into Opioid Peptidomimetics.
Bender AM, Griggs NW, Gao C, Trask TJ, Traynor JR, Mosberg HI. Bender AM, et al. ACS Med Chem Lett. 2015 Oct 19;6(12):1199-203. doi: 10.1021/acsmedchemlett.5b00344. eCollection 2015 Dec 10. ACS Med Chem Lett. 2015. PMID: 26713104 Free PMC article.
Discovery of a Potent Highly Biased MOR Partial Agonist among Diastereomeric C9-Hydroxyalkyl-5-phenylmorphans.
Lutz JA, Sulima A, Gutman ES, Bow EW, Luo D, Kaska S, Prisinzano TE, Paronis CA, Bergman J, Imler GH, Kerr AT, Jacobson AE, Rice KC. Lutz JA, et al. Molecules. 2023 Jun 15;28(12):4795. doi: 10.3390/molecules28124795. Molecules. 2023. PMID: 37375350 Free PMC article.
Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery.
Lee YS. Lee YS. Biomolecules. 2022 Sep 5;12(9):1241. doi: 10.3390/biom12091241. Biomolecules. 2022. PMID: 36139079 Free PMC article. Review.

See all "Cited by" articles

References

1. Lowery JJ, Raymond TJ, Giuvelis D, Bidlack JM, Polt R, Bilsky EJ. In Vivo Characterization of MMP-2200, a Mixed δ/µ Opioid Agonist, In Mice. J. Pharmacol. Exp. Ther. 2011;336:767–778. - PMC - PubMed
1. Abdelhamid EE, Sultana M, Portoghese PS, Takemori AE. Selective Blockage of the Delta Opioid Receptors Prevents the Development of Morphine Tolerance and Dependence in Mice. J. Pharmacol. Exp. Ther. 1991;258:299–303. - PubMed
1. Schiller PW, Fundytus ME, Merovitz L, Weltrowska G, Nguyen TM, Lemieux C, Chung NN, Coderre TJ. The Opioid mu Agonist/delta Antagonist DIPP-NH(2)[Psi] Produces a Potent Analgesic Effect, No Physical Dependence, and Less Tolerance than Morphine in Rats. J. Med. Chem. 1999;42:3520–3526. - PubMed
1. Ananthan S, Saini SK, Dersch CM, Xu H, McGlinchey N, Giuvelis D, Bilsky EJ, Rothman RB. 14-Alkoxy- and 14- Acyloxypyridomorphinans: µ Agonist/δ Antagonist Opioid Analgesics with Diminished Tolerance and Dependence Side Effects. J. Med. Chem. 2012;55:8350–8363. - PMC - PubMed
1. Breslin HJ, Diamond CJ, Kavash RW, Cai C, Dyatkin AB, Miskowski TA, Zhang S, Wade PR, Hornby PJ, He W. Identification of a Dual δ OR Antagonist/µ OR Agonist as a Potential Therapeutic for Diarrhea-Predominant Irritable Bowel Syndrome (IBS-d) Bioorg. Med. Chem. Lett. 2012;22:4869–4872. - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- scite Smart Citations
Chemical Information
- BindingDB
Research Materials
- NCI CPTC Antibody Characterization Program

[1] Lowery JJ, Raymond TJ, Giuvelis D, Bidlack JM, Polt R, Bilsky EJ. In Vivo Characterization of MMP-2200, a Mixed δ/µ Opioid Agonist, In Mice. J. Pharmacol. Exp. Ther. 2011;336:767–778. - PMC - PubMed

[2] Lowery JJ, Raymond TJ, Giuvelis D, Bidlack JM, Polt R, Bilsky EJ. In Vivo Characterization of MMP-2200, a Mixed δ/µ Opioid Agonist, In Mice. J. Pharmacol. Exp. Ther. 2011;336:767–778. - PMC - PubMed

[3] Abdelhamid EE, Sultana M, Portoghese PS, Takemori AE. Selective Blockage of the Delta Opioid Receptors Prevents the Development of Morphine Tolerance and Dependence in Mice. J. Pharmacol. Exp. Ther. 1991;258:299–303. - PubMed

[4] Abdelhamid EE, Sultana M, Portoghese PS, Takemori AE. Selective Blockage of the Delta Opioid Receptors Prevents the Development of Morphine Tolerance and Dependence in Mice. J. Pharmacol. Exp. Ther. 1991;258:299–303. - PubMed

[5] Schiller PW, Fundytus ME, Merovitz L, Weltrowska G, Nguyen TM, Lemieux C, Chung NN, Coderre TJ. The Opioid mu Agonist/delta Antagonist DIPP-NH(2)[Psi] Produces a Potent Analgesic Effect, No Physical Dependence, and Less Tolerance than Morphine in Rats. J. Med. Chem. 1999;42:3520–3526. - PubMed

[6] Schiller PW, Fundytus ME, Merovitz L, Weltrowska G, Nguyen TM, Lemieux C, Chung NN, Coderre TJ. The Opioid mu Agonist/delta Antagonist DIPP-NH(2)[Psi] Produces a Potent Analgesic Effect, No Physical Dependence, and Less Tolerance than Morphine in Rats. J. Med. Chem. 1999;42:3520–3526. - PubMed

[7] Ananthan S, Saini SK, Dersch CM, Xu H, McGlinchey N, Giuvelis D, Bilsky EJ, Rothman RB. 14-Alkoxy- and 14- Acyloxypyridomorphinans: µ Agonist/δ Antagonist Opioid Analgesics with Diminished Tolerance and Dependence Side Effects. J. Med. Chem. 2012;55:8350–8363. - PMC - PubMed

[8] Ananthan S, Saini SK, Dersch CM, Xu H, McGlinchey N, Giuvelis D, Bilsky EJ, Rothman RB. 14-Alkoxy- and 14- Acyloxypyridomorphinans: µ Agonist/δ Antagonist Opioid Analgesics with Diminished Tolerance and Dependence Side Effects. J. Med. Chem. 2012;55:8350–8363. - PMC - PubMed

[9] Breslin HJ, Diamond CJ, Kavash RW, Cai C, Dyatkin AB, Miskowski TA, Zhang S, Wade PR, Hornby PJ, He W. Identification of a Dual δ OR Antagonist/µ OR Agonist as a Potential Therapeutic for Diarrhea-Predominant Irritable Bowel Syndrome (IBS-d) Bioorg. Med. Chem. Lett. 2012;22:4869–4872. - PubMed

[10] Breslin HJ, Diamond CJ, Kavash RW, Cai C, Dyatkin AB, Miskowski TA, Zhang S, Wade PR, Hornby PJ, He W. Identification of a Dual δ OR Antagonist/µ OR Agonist as a Potential Therapeutic for Diarrhea-Predominant Irritable Bowel Syndrome (IBS-d) Bioorg. Med. Chem. Lett. 2012;22:4869–4872. - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Synthesis and evaluation of 4-substituted piperidines and piperazines as balanced affinity μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands

Affiliations

Synthesis and evaluation of 4-substituted piperidines and piperazines as balanced affinity μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands

Authors

Affiliations

Abstract

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Chemical Information

Research Materials

Abstract

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Chemical Information

Research Materials