Synthesis of CJ-15,208, a novel κ-opioid receptor antagonist

Ross, Nicolette C.; Kulkarni, Santosh S.; McLaughlin, Jay P.; Aldrich, Jane V.

doi:10.1016/j.tetlet.2010.07.086

Cited by 27 publications

(60 citation statements)

References 24 publications

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“…The sources of reagents, amino acids, 2-chlorotrityl chloride resin and solvents are the same as reported previously (Ross et al, 2010;Aldrich et al, 2011). Amino acids are the L-isomer unless otherwise specified and abbreviations for amino acids follow the IUPAC-IUB Joint Commission of Biochemical Nomenclature [Eur J Biochem (1984) Figure 1) were dissolved daily prior to administration initially in dimethyl sulfoxide (DMSO), and sufficient warm (40°C) sterile saline (0.9% ) then added so that the final vehicle for in vivo administration consisted of one part DMSO and one part sterile saline.…”

Section: Methodsmentioning

confidence: 99%

“…The linear peptide precursors (based on the parent sequence H-D-Trp-Phe-D-Pro-Phe-OH with substitution of D-Ala, Ala, D-NMeAla and Ala in positions 1-4, respectively) were synthesized on a 2-chlorotrityl choride resin by Fmoc solid phase synthesis, and the peptides cleaved from the resin with 1% trifluoroacetic acid in dichloromethane as described previously (Ross et al, 2010;Aldrich et al, 2011). The crude linear peptides were used in the cyclization reactions without further purification.…”

Section: Peptide Synthesis and Purificationmentioning

confidence: 99%

“…The crude linear peptides were used in the cyclization reactions without further purification. The peptides were initially cyclized using the previously reported procedure (Ross et al, 2010;Aldrich et al, 2011). This procedure was subsequently modified as follows to increase the yields of the cyclic peptides : the crude linear peptide (1 equiv, 0.62 mM in 20 mL N,N-dimethylformamide, DMF) was added dropwise at a rate of 1.4 mL·h −1 (using a KD Scientific single infusion syringe pump, Lab Source Inc., Romeoville, IL, USA) to a dilute solution of HATU [2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 1.5 equiv, 0.938 mM] and N,N-diisopropylethylamine (8 equiv, 5 mM) in DMF.…”

Section: Peptide Synthesis and Purificationmentioning

confidence: 99%

“…Because the stereochemistry of the Trp residue in CJ-15,208 was not determined when this natural product was isolated, we synthesized both tryptophan isomers of this macrocyclic peptide (Kulkarni et al, 2009;Ross et al, 2010), and found that the peptide containing L-Trp was the natural product based on its optical rotation. The D-Trp containing peptide ( Figure 1A) also preferentially bound to KOP receptors and exhibited antagonist activity at these receptors, both in vitro (Dolle et al, 2009;Ross et al, 2010; and in vivo (Ross et al, 2012;Eans et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…The D-Trp containing peptide ( Figure 1A) also preferentially bound to KOP receptors and exhibited antagonist activity at these receptors, both in vitro (Dolle et al, 2009;Ross et al, 2010; and in vivo (Ross et al, 2012;Eans et al, 2013). Therefore, we are exploring the structure-activity relationships of both Trp isomers of 208.…”

Section: Introductionmentioning

confidence: 99%

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Alanine analogues of [D‐Trp]CJ‐15,208: novel opioid activity profiles and prevention of drug‐ and stress‐induced reinstatement of cocaine‐seeking behaviour

Aldrich

Senadheera

Ross

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEThe novel macrocyclic peptide cyclo [Phe-D-Pro-Phe-D-Trp] ([D-Trp]CJ-15,208) exhibits κ opioid (KOP) receptor antagonist activity in both in vitro and in vivo assays. The four alanine analogues of this peptide were synthesized and characterized both in vitro and in vivo to assess the contribution of different amino acid residues to the activity of [D-Trp]CJ-15,208. EXPERIMENTAL APPROACHThe peptides were synthesized by a combination of solid phase peptide synthesis and cyclization in solution. The analogues were evaluated in vitro in receptor binding and functional assays, and in vivo with mice using a tail-withdrawal assay for antinociceptive and opioid antagonist activity. Mice demonstrating extinction of cocaine conditioned-place preference (CPP) were pretreated with selected analogues to evaluate prevention of stress or cocaine-induced reinstatement of CPP. KEY RESULTSThe alanine analogues displayed pharmacological profiles in vivo distinctly different from [D-Trp]CJ-15,208. While the analogues exhibited varying opioid receptor affinities and κ and μ opioid receptor antagonist activity in vitro, they produced potent opioid receptor-mediated antinociception (ED50 = 0.28-4.19 nmol, i.c.v.) in vivo. Three of the analogues also displayed KOP receptor antagonist activity in vivo. Pretreatment with an analogue exhibiting both KOP receptor agonist and antagonist activity in vivo prevented both cocaine-and stress-induced reinstatement of cocaine-seeking behaviour in the CPP assay in a time-dependent manner. CONCLUSIONS AND IMPLICATIONSThese unusual macrocyclic peptides exhibit in vivo opioid activity profiles different from the parent compound and represent novel compounds for potential development as therapeutics for drug abuse and possibly as analgesics. BJP

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Section: Methodsmentioning

confidence: 99%

Section: Peptide Synthesis and Purificationmentioning

confidence: 99%

Section: Peptide Synthesis and Purificationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Alanine analogues of [D‐Trp]CJ‐15,208: novel opioid activity profiles and prevention of drug‐ and stress‐induced reinstatement of cocaine‐seeking behaviour

Aldrich

Senadheera

Ross

et al. 2014

British J Pharmacology

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Unexpected Opioid Activity Profiles of Analogues of the Novel Peptide Kappa Opioid Receptor Ligand CJ‐15,208

Aldrich¹,

Kulkarni²,

Senadheera³

et al. 2011

ChemMedChem

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An alanine scan was performed on the novel kappa opioid receptor (KOR) peptide ligand CJ-15,208 to determine which residues contribute to the potent in vivo agonist activity observed for the parent peptide. These cyclic tetrapeptides were synthesized by a combination of solid phase peptide synthesis of the linear precursors, followed by cyclization in solution. Like the parent peptide, each of the analogs exhibited agonist activity and KOR antagonist activity in an antinociceptive assay in vivo. Unlike the parent peptide, the agonist activity of the potent analogs was mediated predominantly if not exclusively by mu opioid receptors (MOR). Thus analogs 2 and 4, in which one of the phenylalanine residues was replaced by alanine, exhibited both potent MOR agonist activity and KOR antagonist activity in vivo. These peptides represent novel lead compounds for the development of peptide-based opioid analgesics.

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Synthesis and Applications of Peptides and Peptidomimetics in Drug Discovery

JIMMIDI

2023

Eur J Org Chem

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Peptides are described as naturally occurring short chains of amino acids and offer great potential as therapeutic agents because of their target selectivity, safe, and well tolerable. Hence, there is an increased interest in peptides in pharmaceutical research and development and approximately more than 170 peptide therapeutics are currently being evaluated in clinical trials and many are being used as therapeutic drugs for various diseases including COVID‐19. The present Review article focuses on recent progress in peptide drug discovery and advancements in synthetic methodologies to enhance their stability and physiological activity of peptides and as well peptidomimetics.

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Synthesis of CJ-15,208, a novel κ-opioid receptor antagonist

Cited by 27 publications

References 24 publications

Alanine analogues of [D‐Trp]CJ‐15,208: novel opioid activity profiles and prevention of drug‐ and stress‐induced reinstatement of cocaine‐seeking behaviour

Alanine analogues of [D‐Trp]CJ‐15,208: novel opioid activity profiles and prevention of drug‐ and stress‐induced reinstatement of cocaine‐seeking behaviour

Unexpected Opioid Activity Profiles of Analogues of the Novel Peptide Kappa Opioid Receptor Ligand CJ‐15,208

Synthesis and Applications of Peptides and Peptidomimetics in Drug Discovery

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