Identification of c[D-Trp-Phe-β-Ala-β-Ala], the First κ-Opioid Receptor-Specific Negative Allosteric Modulator.

Recently, the fungus secondary metabolite cyclotetrapetide c[Trp-Phe-D-Pro-Phe] (CJ-15,208) and its derivatives deserved some attention for their unusual structure and distinctive in vitro and in vivo activity. These tryptophan-containing noncationic opioid peptides can be truly regarded as versatile picklocks capable of activating all opioid receptors. Intriguingly, minimal modification of the potent κ-opioid receptor (KOR) agonist c[D-Trp-Phe-Gly-β-Ala] (3) yielded c[D-Trp-Phe-β-Ala-β-Ala] (11), the first KOR-specific negative allosteric modulator (NAM) reported to-date. KOR exerts control over numerous functions in the central nervous system, including pain, depression, stress, mood, and reward. Hence, this KOR-selective NAM looks promising for modulating the KOR in addiction and neuropsychiatric disorders.