Details

Autor(en) / Beteiligte

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

Titel

Novel opioid cyclic tetrapeptides: Trp isomers of CJ-15,208 exhibit distinct opioid receptor agonism and short-acting [kappa] opioid receptor antagonism

Ist Teil von

• British journal of pharmacology, 2012-02, Vol.165 (4b), p.1097-1108

Ort / Verlag

London: Blackwell Publishing Ltd

Erscheinungsjahr

2012

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• BACKGROUND AND PURPOSE The [kappa] opioid receptor antagonists demonstrate potential for maintaining abstinence from psychostimulant abuse, but existing non-peptide [kappa]-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 [kappa]-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 GTP[gamma]S 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 [kappa]-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 [kappa] receptors (Ki 30-35 nM) as well as [kappa] receptor antagonism in vitro. As expected, the D-Trp cyclic tetrapeptide exhibited minimal agonist activity and induced dose-dependent [kappa]-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 [kappa] 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. [PUBLICATION ABSTRACT]