Novel opioid cyclic tetrapeptides

Trp isomers of CJ-15,208 exhibit distinct opioid receptor agonism and short-acting κ opioid receptor antagonism

Nicolette C. Ross, Kate J. Reilley, Thomas F. Murray, Jane V. Aldrich, Jay P. McLaughlin

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE The κ opioid receptor antagonists demonstrate potential for maintaining abstinence from psychostimulant abuse, but existing non-peptide κ-receptor selective antagonists show exceptionally long activity. We hypothesized that the L- and D-Trp isomers of CJ-15,208, a natural cyclic tetrapeptide reported to be a κ-receptor antagonist in vitro, would demonstrate short-acting, dose-dependent antagonism in vivo, preventing reinstatement of cocaine-seeking behaviour. EXPERIMENTAL APPROACH Affinity, selectivity and efficacy of the L-Trp and D-Trp isomers for opioid receptors were assessed in vitro in radioligand and GTPγS binding assays. Opioid receptor agonist and antagonist activities were characterized in vivo following i.c.v. administration with the 55°C warm water tail-withdrawal assay. The D-Trp isomer, which demonstrated primarily κ-receptor selective antagonist activity, was further evaluated for its prevention of stress- and drug-induced reinstatement of extinguished cocaine conditioned place preference (CPP). KEY RESULTS The two isomers showed similar affinity and selectivity for κ receptors (K i 30-35 nM) as well as κ receptor antagonism in vitro. As expected, the D-Trp cyclic tetrapeptide exhibited minimal agonist activity and induced dose-dependent κ-receptor selective antagonism lasting less than 18 h in vivo. Pretreatment with this peptide prevented stress-, but not cocaine-induced, reinstatement of extinguished cocaine CPP. In contrast, the L-Trp cyclic tetrapeptide unexpectedly demonstrated mixed opioid agonist/antagonist activity. CONCLUSIONS AND IMPLICATIONS The L-Trp and the D-Trp isomers of CJ-15,208 demonstrate stereospecific opioid activity in vivo. The relatively brief κ opioid receptor antagonism, coupled with the prevention of stress-induced reinstatement of extinguished cocaine-seeking behaviour, suggests the D-Trp isomer could be used therapeutically to maintain abstinence from psychostimulant abuse.

Original languageEnglish
Pages (from-to)1097-1108
Number of pages12
JournalBritish Journal of Pharmacology
Volume165
Issue number4 B
DOIs
StatePublished - Feb 2012

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Opioid Receptors
Cocaine
Opioid Analgesics
Narcotic Antagonists
CJ 15,208
Peptides
Water
Pharmaceutical Preparations
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Novel opioid cyclic tetrapeptides : Trp isomers of CJ-15,208 exhibit distinct opioid receptor agonism and short-acting κ opioid receptor antagonism. / Ross, Nicolette C.; Reilley, Kate J.; Murray, Thomas F.; Aldrich, Jane V.; McLaughlin, Jay P.

In: British Journal of Pharmacology, Vol. 165, No. 4 B, 02.2012, p. 1097-1108.

Research output: Contribution to journalArticle

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abstract = "BACKGROUND AND PURPOSE The κ opioid receptor antagonists demonstrate potential for maintaining abstinence from psychostimulant abuse, but existing non-peptide κ-receptor selective antagonists show exceptionally long activity. We hypothesized that the L- and D-Trp isomers of CJ-15,208, a natural cyclic tetrapeptide reported to be a κ-receptor antagonist in vitro, would demonstrate short-acting, dose-dependent antagonism in vivo, preventing reinstatement of cocaine-seeking behaviour. EXPERIMENTAL APPROACH Affinity, selectivity and efficacy of the L-Trp and D-Trp isomers for opioid receptors were assessed in vitro in radioligand and GTPγS binding assays. Opioid receptor agonist and antagonist activities were characterized in vivo following i.c.v. administration with the 55°C warm water tail-withdrawal assay. The D-Trp isomer, which demonstrated primarily κ-receptor selective antagonist activity, was further evaluated for its prevention of stress- and drug-induced reinstatement of extinguished cocaine conditioned place preference (CPP). KEY RESULTS The two isomers showed similar affinity and selectivity for κ receptors (K i 30-35 nM) as well as κ receptor antagonism in vitro. As expected, the D-Trp cyclic tetrapeptide exhibited minimal agonist activity and induced dose-dependent κ-receptor selective antagonism lasting less than 18 h in vivo. Pretreatment with this peptide prevented stress-, but not cocaine-induced, reinstatement of extinguished cocaine CPP. In contrast, the L-Trp cyclic tetrapeptide unexpectedly demonstrated mixed opioid agonist/antagonist activity. CONCLUSIONS AND IMPLICATIONS The L-Trp and the D-Trp isomers of CJ-15,208 demonstrate stereospecific opioid activity in vivo. The relatively brief κ opioid receptor antagonism, coupled with the prevention of stress-induced reinstatement of extinguished cocaine-seeking behaviour, suggests the D-Trp isomer could be used therapeutically to maintain abstinence from psychostimulant abuse.",
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