Nascent structure–activity relationship study of a diastereomeric series of kappa opioid receptor antagonists derived from CJ-15,208

Dolle, Roland E.; Michaut, Mathieu; Martinez-Teipel, Blanca; Seida, Pamela R.; Ajello, Christopher W.; Müller, Alison; DeHaven, Robert N.; Carroll, Patrick J.

doi:10.1016/j.bmcl.2009.04.105

Cited by 32 publications

(81 citation statements)

References 16 publications

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“…Analogues 3 and 4 exhibited intermediate affinities for KOP receptors, 3.5-and 7.7-fold lower than that of analogue 1. Similar results were reported by Dolle et al (2009) for analogues 2 and 5, but the KOP receptor affinity of analogue 4 found here (167 nM) is substantially higher than that reported by Dolle et al (2009) (Ki = 1300 nM). (Note that analogue 3 has not been previously reported.…”

Section: In Vitro Pharmacological Evaluationsupporting

confidence: 90%

“…Analogue 2 exhibited potent antagonist activity at KOP receptors (KB = 0.8 nM), consistent with the report by Dolle et al (2009). The potencies of the other analogues as KOP receptor antagonists in this assay generally paralleled their receptor affinities.…”

Section: In Vitro Pharmacological Evaluationsupporting

confidence: 76%

“…MOP receptor affinity was generally less sensitive to alanine substitution in the macrocyclic tetrapeptide than was affinity for the KOP receptor ( Dolle et al (2009), although those authors reported substantially lower affinity (Ki > 2 μM) for peptide 4. None of the analogues showed appreciable affinity for DOP receptors in the binding assay.…”

Section: In Vitro Pharmacological Evaluationmentioning

confidence: 97%

“…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: In Vitro Pharmacological Evaluationsupporting

confidence: 90%

Section: In Vitro Pharmacological Evaluationsupporting

confidence: 76%

Section: In Vitro Pharmacological Evaluationmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…The peptide natural product CJ-15,208 was reported to antagonize a KOR agonist in vitro (Saito et al, 2002). The Land D-Trp stereoisomers of this macrocyclic tetrapeptide were synthesized (Dolle et al, 2009;Kulkarni et al, 2009;Ross et al, 2010), and both found to bind to KOR with similar affinities in radioligand receptor-binding experiments (Dolle et al, 2009;Kulkarni et al, 2009;Ross et al, 2010; (Dolle et al, 2009;Ross et al, 2012) and also exhibits KOR antagonism in vivo, preventing the reinstatement of extinguished cocaine conditioned place preference (CPP) after i.c.v. administration (Ross et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

The macrocyclic tetrapeptide [D‐Trp]CJ‐15,208 produces short‐acting κ opioid receptor antagonism in the CNS after oral administration

Eans

Ganno

Reilley

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSECyclic peptides are resistant to proteolytic cleavage, therefore potentially exhibiting activity after systemic administration. We hypothesized that the macrocyclic k opioid receptor ( CONCLUSIONS AND IMPLICATIONSThe macrocyclic tetrapeptide [D-Trp]CJ-15,208 is a short-duration KOR antagonist with weak KOR agonist activity that is active after oral administration and demonstrates blood-brain barrier permeability. These data validate the use of systemically active peptides such as [D-Trp]CJ-15,208 as potentially useful therapeutics. Abbreviations

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Understanding and designing head‐to‐tail cyclic peptides

2018

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Cyclic peptides (CPs) are an exciting class of molecules with a variety of applications. However, design strategies for CP therapeutics, for example, are generally limited by a poor understanding of their sequence-structure relationships. This knowledge gap often leads to a trial-and-error approach for designing CPs for a specific purpose, which is both costly and time-consuming. Herein, we describe the current experimental and computational efforts in understanding and designing head-to-tail CPs along with their respective challenges. In addition, we provide several future directions in the field of computational CP design to improve its accuracy, efficiency and applicability. These advances, combined with experimental techniques, shall ultimately provide a better understanding of these interesting molecules and a reliable working platform to rationally design CPs with desired characteristics.

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Nascent structure–activity relationship study of a diastereomeric series of kappa opioid receptor antagonists derived from CJ-15,208

Cited by 32 publications

References 16 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

The macrocyclic tetrapeptide [D‐Trp]CJ‐15,208 produces short‐acting κ opioid receptor antagonism in the CNS after oral administration

Understanding and designing head‐to‐tail cyclic peptides

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