An analog of [d-Trp]CJ-15,208 exhibits kappa opioid receptor antagonism following oral administration and prevents stress-induced reinstatement of extinguished morphine conditioned place preference
Copyright © 2022 Elsevier Inc. All rights reserved..
Opioid use disorder (OUD) relapse rates are discouragingly high, underscoring the need for new treatment options. The macrocyclic tetrapeptide natural product CJ-15,208 and its stereoisomer [d-Trp]CJ-15,208 demonstrate kappa opioid receptor (KOR) antagonist activity upon oral administration which prevents stress-induced reinstatement of cocaine-seeking behavior. In order to further explore the structure-activity relationships and expand the potential therapeutic applications of KOR antagonism for the treatment of OUD, we screened a series of 24 analogs of [d-Trp]CJ-15,208 with the goal of enhancing KOR antagonist activity. From this screening, analog 22 arose as a compound of interest, demonstrating dose-dependent KOR antagonism after central and oral administration lasting at least 2.5 h. In further oral testing, analog 22 lacked respiratory, locomotor, or reinforcing effects, consistent with the absence of opioid agonism. Pretreatment with analog 22 (30 mg/kg, p.o.) prevented stress-induced reinstatement of extinguished morphine conditioned place preference and reduced some signs of naloxone-precipitated withdrawal in mice physically dependent on morphine. Collectively, these data support the therapeutic potential of KOR antagonists to support abstinence in OUD and ameliorate opioid withdrawal.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:217 |
|---|---|
| Enthalten in: |
Pharmacology, biochemistry, and behavior - 217(2022) vom: 21. Juni, Seite 173405 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Brice-Tutt, Ariana C [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 14.06.2022 Date Revised 28.02.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.pbb.2022.173405 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM341074926 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM341074926 | ||
| 003 | DE-627 | ||
| 005 | 20240229165915.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.pbb.2022.173405 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1310.xml |
| 035 | |a (DE-627)NLM341074926 | ||
| 035 | |a (NLM)35584724 | ||
| 035 | |a (PII)S0091-3057(22)00084-3 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Brice-Tutt, Ariana C |e verfasserin |4 aut | |
| 245 | 1 | 3 | |a An analog of [d-Trp]CJ-15,208 exhibits kappa opioid receptor antagonism following oral administration and prevents stress-induced reinstatement of extinguished morphine conditioned place preference |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 14.06.2022 | ||
| 500 | |a Date Revised 28.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 Elsevier Inc. All rights reserved. | ||
| 520 | |a Opioid use disorder (OUD) relapse rates are discouragingly high, underscoring the need for new treatment options. The macrocyclic tetrapeptide natural product CJ-15,208 and its stereoisomer [d-Trp]CJ-15,208 demonstrate kappa opioid receptor (KOR) antagonist activity upon oral administration which prevents stress-induced reinstatement of cocaine-seeking behavior. In order to further explore the structure-activity relationships and expand the potential therapeutic applications of KOR antagonism for the treatment of OUD, we screened a series of 24 analogs of [d-Trp]CJ-15,208 with the goal of enhancing KOR antagonist activity. From this screening, analog 22 arose as a compound of interest, demonstrating dose-dependent KOR antagonism after central and oral administration lasting at least 2.5 h. In further oral testing, analog 22 lacked respiratory, locomotor, or reinforcing effects, consistent with the absence of opioid agonism. Pretreatment with analog 22 (30 mg/kg, p.o.) prevented stress-induced reinstatement of extinguished morphine conditioned place preference and reduced some signs of naloxone-precipitated withdrawal in mice physically dependent on morphine. Collectively, these data support the therapeutic potential of KOR antagonists to support abstinence in OUD and ameliorate opioid withdrawal | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Antagonist | |
| 650 | 4 | |a Kappa opioid receptor | |
| 650 | 4 | |a Macrocyclic peptide | |
| 650 | 4 | |a Opioid use disorder | |
| 650 | 4 | |a Reinstatement | |
| 650 | 4 | |a Withdrawal | |
| 650 | 7 | |a Analgesics, Opioid |2 NLM | |
| 650 | 7 | |a CJ 15,208 |2 NLM | |
| 650 | 7 | |a Narcotic Antagonists |2 NLM | |
| 650 | 7 | |a Peptides, Cyclic |2 NLM | |
| 650 | 7 | |a Receptors, Opioid, kappa |2 NLM | |
| 650 | 7 | |a Morphine |2 NLM | |
| 650 | 7 | |a 76I7G6D29C |2 NLM | |
| 700 | 1 | |a Eans, Shainnel O |e verfasserin |4 aut | |
| 700 | 1 | |a Yakovlev, Dmitry |e verfasserin |4 aut | |
| 700 | 1 | |a Aldrich, Jane V |e verfasserin |4 aut | |
| 700 | 1 | |a McLaughlin, Jay P |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Pharmacology, biochemistry, and behavior |d 1973 |g 217(2022) vom: 21. Juni, Seite 173405 |w (DE-627)NLM000022721 |x 1873-5177 |7 nnns |
| 773 | 1 | 8 | |g volume:217 |g year:2022 |g day:21 |g month:06 |g pages:173405 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.pbb.2022.173405 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 217 |j 2022 |b 21 |c 06 |h 173405 | ||