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

Junwei Zhao; Monica Baiula; Elisabetta Cuna; Marco Francescato; Joanna Matalińska; Piotr F J Lipiński; Andrea Bedini; Luca Gentilucci

doi:10.1021/acsptsci.4c00372

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

ACS Pharmacol Transl Sci. 2024 Sep 11;7(10):3192-3204. doi: 10.1021/acsptsci.4c00372. eCollection 2024 Oct 11.

Authors

Junwei Zhao¹, Monica Baiula², Elisabetta Cuna², Marco Francescato¹, Joanna Matalińska³, Piotr F J Lipiński³, Andrea Bedini², Luca Gentilucci^{1

4}

Affiliations

¹ Dept. of Chemistry "G. Ciamician", University of Bologna, Campus Navile - Ue4, via Gobetti 83, Bologna 40129, Italy.
² Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy.
³ Department of Neuropeptides, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawinskiego Street, Warsaw 02-106, Poland.
⁴ Health Sciences & Technologies (HST) CIRI, University of Bologna, Ozzano Emilia 40064, Italy.

PMID: 39416958
PMCID: PMC11475277 (available on 2025-09-11)
DOI: 10.1021/acsptsci.4c00372

Abstract

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.