Structure–Activity Relationships of [des-Arg⁷]Dynorphin A Analogues at the κ Opioid Receptor

Abstract

Dynorphin A (Dyn A) is an endogenous ligand for the opioid receptors with preference for the κ opioid receptor (KOR), and its structure–activity relationship (SAR) has been extensively studied at the KOR to develop selective potent agonists and antagonists. Numerous SAR studies have revealed that the Arg 7 residue is essential for KOR activity. In contrast, our systematic SAR studies on [des-Arg 7 ]Dyn A analogues found that Arg 7 is not a key residue and even deletion of the residue does not affect biological activities at the KOR. In addition, it was also found that [des-Arg 7 ]Dyn A(1–9)-NH 2 is a minimum pharmacophore and its modification at the N-terminus leads to selective KOR antagonists. A lead ligand, 14, with high affinity and antagonist activity showed improved metabolic stability and could block antinociceptive effects of a KOR selective agonist, FE200665, in vivo, indicating high potential to treat KOR mediated disorders such as stress-induced relapse.