Optimization of the Macrocyclic Tetrapeptide [D-Trp]CJ-15,208 to Prevent Stress-Induced Relapse of Cocaine-Seeking Behavior

TL;DR

Scientists optimized a drug to block stress-triggered relapse in cocaine addiction by improving its brain-penetrating properties.

Contribution

The study introduces optimized macrocyclic tetrapeptide analogs with enhanced potency and lower required doses for KOR antagonism.

Findings

Substituted analogs of [D-Trp]CJ-15,208 showed significant KOR antagonism in vivo after oral administration.

Lower doses of [D-Phe4]CJ-15,208 and [D-Trp(formamide)]CJ-15,208 effectively prevented stress-induced cocaine-seeking behavior in mice.

The optimized peptides demonstrated improved efficacy compared to the original compound.

Abstract

Kappa opioid receptor (KOR) antagonists may have therapeutic potential to prevent stress-induced relapse in abstinent individuals with cocaine use disorder (CUD). The macrocyclic peptide [D-Trp]CJ-15,208 (cyclo[Phe-D-Pro-Phe-D-Trp]) is an orally bioavailable, brain–penetrant selective KOR antagonist that prevents stress-induced reinstatement of cocaine-seeking behavior in a mouse model of CUD. We synthesized and evaluated analogs of this lead compound with substitutions for the D-Trp residue to identify analogs that exhibit more potent central KOR antagonism following oral administration. The peptides were synthesized by a combination of solid phase and solution peptide synthetic methodologies, and their pharmacological activity was evaluated both in vitro (for KOR affinity, selectivity and antagonism) and in vivo (for antinociception and KOR antagonism), with promising analogs evaluated for their ability to prevent stress-induced reinstatement of cocaine-seeking behavior in the mouse conditioned place preference (CPP) assay. A variety of substituted D-Phe or modified D-Trp derivatives were tolerated by KOR with retention of significant KOR antagonism in vivo after oral administration. Macrocyclic peptide pretreatment, per os, significantly prevented stress-induced reinstatement of cocaine CPP at doses of 10 and 30 mg/kg of [D-Phe4]CJ-15,208, 4, and 30 mg/kg of [D-Trp(formamide)]CJ-15,208, 3, which are 6-fold and 2-fold lower, respectively, than that needed for {D-Trp]CJ-15,208.

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