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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 Arg⁷ residue is essential for KOR activity. In contrast, our systematic SAR studies on [des-Arg⁷]Dyn A analogues found that Arg⁷ 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-Arg⁷]Dyn A(1–9)-NH₂ 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 …