Opioid system research probe (CHEMBL1172245)
A lab-made molecule used by scientists to study pain-signaling receptors in the brain; an experimental research tool, not an approved medicine.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
CHEMBL1172245 is a synthetic research compound designed as a multi-target probe for the opioid system, with particular activity at the delta opioid receptor (OPRD1). It was created by Lee and colleagues at the University of Arizona as part of a program to build a single molecule that simultaneously engages opioid, cholecystokinin (CCK), and melanocortin receptors — three receptor systems that interact in the brain's pain-processing circuitry (Lee et al., Bioorg Med Chem Lett, 2010). The compound is not a drug candidate; it is a laboratory tool for studying multi-receptor pain pharmacology. The stored sequence HRWKDF captures the six-residue melanocortin-pharmacophore-derived chain, but the actual compound contains D-4-chlorophenylalanine at position 2 (encoded as standard amino acid in the raw sequence), a C-terminal amide cap, and is conjugated to a Tyr-D-Ala-Gly-Phe enkephalin segment — all modifications absent from the raw sequence shown here.
History
The compound comes from a 2010 paper by Lee, Fernandes, Kulkarani, Mayorov, Davis, Ma, Brown, Gillies, Lai, Porreca, and Hruby, published in Bioorganic & Medicinal Chemistry Letters (Lee et al., 2010). The research program was motivated by two convergent lines of evidence. First, CCK acts as an endogenous suppressor of opioid analgesia in the spinal cord and brainstem: co-administration of CCK receptor antagonists with morphine enhances analgesic potency and slows tolerance development. Second, Hruby's group had previously shown that opioid and melanocortin receptor pharmacophores share structural overlap, making it theoretically possible to encode both receptor contacts in a single peptide scaffold. CHEMBL1172245 was one of approximately fifteen compounds synthesized and tested in that effort, assembled by solid-phase peptide synthesis under microwave-assisted conditions using Rink-amide resin (Lee et al., 2010).
What it does
CHEMBL1172245 binds and activates delta and mu opioid receptors in the low nanomolar range. In radioligand displacement assays it showed an IC50 of 7.943 nM and a Ki of 3.5 nM at the human delta opioid receptor, and an IC50 of 31.62 nM and a Ki of 7.4 nM at the rat mu opioid receptor (Lee et al., Bioorg Med Chem Lett, 2010, as recorded in ChEMBL). In functional isolated-tissue assays it produced agonist responses at the delta receptor in mouse vas deferens (IC50 = 240 nM) and at the mu receptor in guinea pig ileum (IC50 = 330 nM). Despite the design intent, it was not active at CCK-1 or CCK-2 receptors in binding competition assays at 1 μM (Lee et al., 2010).
The delta opioid receptor belongs to the inhibitory G-protein-coupled receptor family (Gi/Go class). Activation suppresses adenylate cyclase, reduces cAMP levels, inhibits voltage-gated calcium channels, and opens inwardly rectifying potassium channels — a combination that decreases nociceptive neurotransmitter release from presynaptic terminals. Delta receptor agonism is particularly relevant to chronic, inflammatory, and neuropathic pain, where delta receptor tone appears to modulate persistent pain hypersensitivity; it also plays a role in mood regulation, with delta agonists showing anxiolytic and antidepressant-like effects in preclinical models.
Evidence
- Human: No human studies. CHEMBL1172245 is a research compound characterized in cell-based and isolated-tissue assays only.
- Animal: No in vivo animal pharmacology data reported for this specific compound.
- In vitro: Binding IC50 = 7.943 nM and Ki = 3.5 nM at human OPRD1; IC50 = 31.62 nM and Ki = 7.4 nM at rat OPRM1; functional agonist activity in mouse MVD (delta, IC50 = 240 nM) and guinea pig GPI (mu, IC50 = 330 nM). Not active at CCK-1 or CCK-2 receptors in binding assays at 1 μM. All data from Lee et al. (Bioorg Med Chem Lett, 2010), as catalogued in ChEMBL (CHEMBL1172245).
Known effects
- Delta opioid receptor agonism — Binding and functional agonist activity confirmed in vitro (Lee et al., 2010)
- Mu opioid receptor agonism — Secondary activity confirmed in binding and functional assays (Lee et al., 2010)
- CCK receptor activity — Not active at CCK-1 or CCK-2 in binding competition assays (Lee et al., 2010)
Regulatory status
- US: Not approved. Research compound only; no IND or clinical development stage documented.
- EU: Not approved.
- WADA: Peptide opioid receptor agonists are prohibited under the Prohibited List (S4, hormone and metabolic modulators / opioids); this specific compound has no registered competitive use context.
Mechanism
CHEMBL1172245 is a conjugate designed around overlapping pharmacophore logic. The HRWKDF-derived chain (PEPTIDE1 in the full structure: His-D-Phe(4-Cl)-Arg-Trp-Lys-Asp-Phe-amide) incorporates the His-Phe-Arg-Trp (HFRW) melanocortin pharmacophore at its N-terminal end — HFRW is the shortest peptide sequence active at melanocortin receptors and is shared by α-MSH and ACTH peptides. This chain is bridged to a Tyr-D-Ala-Gly-Phe enkephalin segment (PEPTIDE2) via a disulfide-type linkage, completing the trivalent design. A third intended contact — CCK receptor blockade — was not observed in binding assays (Lee et al., 2010).
The opioid activity detected (delta IC50 = 7.943 nM) most likely arises from the enkephalin YAGF segment, whose Tyr-Gly-Phe motif is the canonical recognition element for opioid receptors. Delta opioid receptors signal through Gi/Go proteins to suppress cAMP synthesis, inhibit calcium influx, and promote potassium efflux — reducing action potential firing in pain-transmitting neurons. The observed weaker mu receptor activity (IC50 = 31.62 nM) is consistent with the cross-reactivity typical of enkephalin-based scaffolds, which engage both delta and mu subtypes (Lee et al., 2010).
Open questions
- Whether the HFRW-based hexapeptide segment independently contributes melanocortin receptor binding in the full conjugate, or whether this activity is masked by the linker geometry
- No in vivo antinociceptive data have been reported for this compound; efficacy in inflammatory or neuropathic pain models is unknown
- Metabolic stability, serum half-life, and CNS penetration of the conjugate have not been characterized
- Selectivity over the kappa opioid receptor (OPRK1) has not been reported
- Whether separating the two pharmacophore segments would alter the opioid activity profile has not been tested
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Does this short peptide actually bind the opioid receptor on its own, or does it only work when attached to the opioid tail that is missing from the stored sequence?
If the label is wrong, correcting it would prevent wasted experiments chasing a false opioid lead. It would also help researchers correctly identify which part of the original molecule does the opioid work, potentially enabling safer analgesic design.
Could chemically linking the two ends of this peptide into a circular shape make it a more powerful and consistent activator of both its target receptors at once?
Cyclic peptides are generally more stable and potent than linear ones, lasting longer in the body and hitting their targets more reliably. If this approach works, it could yield a research tool, or eventually a drug, that controls pain through two brain circuits simultaneously, potentially requiring lower doses and causing fewer side effects.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| IC50 | 7.943 nM | GPCRDB/ChEMBL |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.691 | global PDE — lower = better |
| disorder | NaN | fraction disordered |
▸3-letter notation
▸recipeboltz-2 1.0
| parameter | value |
|---|---|
| model | boltz-2 1.0 |
| weights | — |
| hardware | nvidia_nim_api |
| mlx version | — |
| python | — |
| random seed | — |
| msa strategy | none |
| diffusion samples | 1 |
| runtime | — |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
▸citationbibtex
@peptide{pep10416,
sequence = {HRWKDF},
target = {oprd1},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}