Design and development of novel, short, stable dynorphin-based opioid agonists for safer analgesic therapy.

ABSTRACT: Kappa opioid receptors have exceptional potential as an analgesic target, seemingly devoid of many problematic Mu receptor side-effects. Kappa-selective, small molecule pharmaceutical agents have been developed, but centrally mediated side-effects limit clinical translation. We modify endogenous dynorphin peptides to improve drug-likeness and develop safer KOP receptor agonists for clinical use. Using rational, iterative design, we developed a series of potent, selective, and metabolically stable peptides from dynorphin 1-7. Peptides were assessed for in vitro cAMP-modulation against three opioid receptors, metabolic stability, KOP receptor selectivity, desensitisation and pERK-signalling capability. Lead peptides were evaluated for in vivo efficacy in a rat model of inflamma

SUBMITTER: Lohman RJ 

PROVIDER: S-EPMC10020352 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature