Dual opioid & hunger-signal research peptide (YGDF / CHEMBL206974)

What this is

YGDF (Tyr-Gly-Asp-Phe) is a four-amino-acid research peptide designed as a minimal "overlapping pharmacophore" ligand that binds at both the mu-opioid receptor (OPRM1) and the cholecystokinin-1 receptor (CCKAR). It emerged from a medicinal-chemistry program that asked: can the message regions of two unrelated peptide hormones — the opioid Tyr-Gly-Gly-Phe motif and the cholecystokinin C-terminal Trp-Met-Asp-Phe motif — be folded into a single short sequence that engages both receptors? YGDF is one of the smallest peptides used as a starting point and reference compound in that line of work. It is a chemical-biology tool, not a therapeutic.

History

The peptide belongs to the broader bifunctional opioid/CCK ligand program led by Victor Hruby's group at the University of Arizona, which spent two decades probing whether single molecules can simultaneously deliver opioid analgesia and CCK antagonism — a combination predicted to blunt the opioid tolerance and dependence driven by anti-opioid CCK signaling. The structure-activity work on short overlapping-pharmacophore peptides at the opioid and cholecystokinin receptors was reported by Agnes and colleagues (Agnes 2006, J. Med. Chem.), in a series whose conceptual frame was laid out in Hruby's earlier interdisciplinary essay on peptide science (Hruby 2003, J. Med. Chem.).

What it does

In binding assays YGDF engages both targets the program was built around: the mu-opioid receptor (the receptor for morphine and the endogenous enkephalins) and the CCK-1 receptor (the receptor for the satiety hormone cholecystokinin). The ChEMBL bioassay record (CHEMBL206974) gives a binding affinity of Ki = 32 nM, placing it in the mid-nanomolar range typical of short designed peptide ligands. Because the sequence is only four residues long and lacks the conformational constraints and modifications used in more refined bifunctional analogs, its activity is best understood as a reference point for SAR rather than as a candidate molecule in its own right.

Evidence

• Human: No human studies.
• Animal: No in-vivo data attached to this card; the parent program reported behavioral pharmacology for more elaborated bifunctional analogs (Agnes 2006).
• In vitro: Binding affinity Ki = 32 nM recorded under ChEMBL assay CHEMBL206974, characterizing this tetrapeptide as part of the overlapping-pharmacophore SAR series.

Mechanism

The design logic is overlap rather than fusion. The classical opioid "message" pharmacophore begins Tyr¹-Gly²-Gly³-Phe⁴ (as in the enkephalins); the cholecystokinin C-terminal "message" pharmacophore ends ...-Trp-Met-Asp-Phe-NH₂. By placing Tyr at the N-terminus and Asp-Phe at the C-terminus of a single short peptide, a four-residue sequence like YGDF presents the minimal Tyr...Phe spacing required for opioid recognition while exposing the Asp-Phe motif that the CCK receptor reads at the other end. The resulting ligand binds at both receptor classes, though potency, subtype selectivity, and functional efficacy at each receptor depend strongly on the residues, stereochemistry, and modifications layered onto this scaffold in the larger Agnes 2006 series.

Related peptides

This card sits inside the broader cholecystokinin family on the platform; the parent hormone and its physiologic role in satiety, gallbladder contraction, and pancreatic enzyme release are described on the CCK card. Bifunctional opioid/CCK ligands are a small, specialized class of designed molecules and do not have a close consumer-facing analog elsewhere in the catalog.