The kappa opioid receptor (KOPr) has exceptional potential as an
analgesic target, seemingly devoid of the many peripheral side-effects
of Mu receptors. Kappa-selective, small molecule pharmaceutical agents
have been developed, but centrally mediated side effects have the
limited their clinical translation. Here, we modify an active endogenous
Dynorphin peptide with the aim of improving drug-likeness and developing
safer KOPr agonists for clinical use. Using rational, iterative design
and modern peptide chemistry, we developed a series of potent, selective
and metabolically stable peptides from Dynorphin 1-7. Peptides were
assessed for cAMP-modulation against Kappa, Mu and Delta opioid
receptors, metabolic stability, KOPr specificity and binding, and
interrogated for in vitro desensitisation and pERK signalling
capability. Finally, lead peptides were evaluated for efficacy in
Freund’s complete adjuvant rat model of inflammatory nociception. A
library of 70 peptides was synthesised and assessed for pharmacological
and metabolic stability factors. At least 10 peptide candidates showed
low nanomolar activity (˂50 nM) in a cAMP assay, specificity for KORr,
and plasma half-life >60 min, with 6 candidates also stable
in trypsin. None of the selected peptides showed pERK activity, with a
bias towards cAMP signalling. In vivo, KA305 and KA311 showed
anti-nociception opioid receptor-specific activity comparable to
morphine and U50 844. These highly potent and metabolically stable
peptides are promising opioid analgesic leads for clinical translation.
Since they are biased peptide KOPr agonists, it is plausible they lack
many of the most significant side effects, such as tolerance, addiction,
sedation and euphoria/dysphoria, common to opioid analgesics.