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

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, selecti

SUBMITTER: Aldrich JV 

PROVIDER: S-EPMC12526156 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature