CJ-15208
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| Category | Antibiotics |
| Catalog number | BBF-02773 |
| CAS | 210236-47-8 |
| Molecular Weight | 577.67 |
| Molecular Formula | C34H35N5O4 |
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Description
CJ-15208 is produced by the strain of Ctenomyces serratus. It selectively inhibits κ-opioid receptor binding with an IC50 of 47 nmol/L.
Specification
| Synonyms | (3S,6S,9S,14aR)-6-((1H-indol-3-yl)methyl)-3,9-dibenzyldecahydropyrrolo[1,2-a][1,4,7,10]tetraazacyclododecine-1,4,7,10-tetraone; c[L-Phe-D-pro-L-Phe-L-trp] |
| IUPAC Name | (3S,6S,9S,12R)-3,9-dibenzyl-6-(1H-indol-3-ylmethyl)-1,4,7,10-tetrazabicyclo[10.3.0]pentadecane-2,5,8,11-tetrone |
| Canonical SMILES | C1CC2C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N2C1)CC3=CC=CC=C3)CC4=CNC5=CC=CC=C54)CC6=CC=CC=C6 |
| InChI | InChI=1S/C34H35N5O4/c40-31-27(18-22-10-3-1-4-11-22)37-33(42)30-16-9-17-39(30)34(43)29(19-23-12-5-2-6-13-23)38-32(41)28(36-31)20-24-21-35-26-15-8-7-14-25(24)26/h1-8,10-15,21,27-30,35H,9,16-20H2,(H,36,40)(H,37,42)(H,38,41)/t27-,28-,29-,30+/m0/s1 |
| InChI Key | GIZJWWQFOGQPRY-GCXHJFECSA-N |
Properties
| Appearance | White Amorphous Powder |
Reference Reading
1. Phenylalanine Stereoisomers of CJ-15,208 and [d-Trp]CJ-15,208 Exhibit Distinctly Different Opioid Activity Profiles
Ariana C Brice-Tutt, Sanjeewa N Senadheera, Michelle L Ganno, Shainnel O Eans, Tanvir Khaliq, Thomas F Murray, Jay P McLaughlin, Jane V Aldrich Molecules. 2020 Sep 2;25(17):3999. doi: 10.3390/molecules25173999.
The macrocyclic tetrapeptide cyclo[Phe-d-Pro-Phe-Trp] (CJ-15,208) and its stereoisomer cyclo[Phe-d-Pro-Phe-d-Trp] exhibit different opioid activity profiles in vivo. The present study evaluated the influence of the Phe residues' stereochemistry on the peptides' opioid activity. Five stereoisomers were synthesized by a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance development, and place conditioning were also assessed in vivo. All of the stereoisomers exhibited antinociception following either intracerebroventricular or oral administration differentially mediated by multiple opioid receptors, with kappa opioid receptor (KOR) activity contributing for all of the peptides. However, unlike the parent peptides, KOR antagonism was exhibited by only one stereoisomer, while another isomer produced DOR antagonism. The stereoisomers of CJ-15,208 lacked significant respiratory effects, while the [d-Trp]CJ-15,208 stereoisomers did not elicit antinociceptive tolerance. Two isomers, cyclo[d-Phe-d-Pro-d-Phe-Trp] (3) and cyclo[Phe-d-Pro-d-Phe-d-Trp] (5), did not elicit either preference or aversion in a conditioned place preference assay. Collectively, these stereoisomers represent new lead compounds for further investigation in the development of safer opioid analgesics.
2. 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
Ariana C Brice-Tutt, Shainnel O Eans, Dmitry Yakovlev, Jane V Aldrich, Jay P McLaughlin Pharmacol Biochem Behav. 2022 Jun;217:173405. doi: 10.1016/j.pbb.2022.173405. Epub 2022 May 15.
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.
3. Peptide Kappa Opioid Receptor Ligands and Their Potential for Drug Development
Jane V Aldrich, Jay P McLaughlin Handb Exp Pharmacol. 2022;271:197-220. doi: 10.1007/164_2021_519.
Ligands for kappa opioid receptors (KOR) have potential uses as non-addictive analgesics and for the treatment of pruritus, mood disorders, and substance abuse. These areas continue to have major unmet medical needs. Significant advances have been made in recent years in the preclinical development of novel opioid peptides, notably ones with structural features that inherently impart stability to proteases. Following a brief discussion of the potential therapeutic applications of KOR agonists and antagonists, this review focuses on two series of novel opioid peptides, all-D-amino acid tetrapeptides as peripherally selective KOR agonists for the treatment of pain and pruritus without centrally mediated side effects, and macrocyclic tetrapeptides based on CJ-15,208 that can exhibit different opioid profiles with potential applications such as analgesics and treatments for substance abuse.
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Bio Calculators
* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C1V1 = C2V2
* Total Molecular Weight:
g/mol
Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳
