Pain-receptor research peptide (CHEMBL1172428)

What this is

CHEMBL1172428 is a synthetic research peptide designed to engage the delta-opioid receptor (DOR, encoded by the OPRD1 gene) — one of the brain and spinal cord's principal pain-modulating receptors. It was engineered as part of a trivalent ligand strategy: a single molecule carrying three distinct pharmacophore segments capable of engaging the opioid, cholecystokinin (CCK), and melanocortin receptor systems at the same time. The card stores the sequence FHRWDF as a six-residue shorthand for the pharmacophore core; the full compound as characterised in ChEMBL is a 10-residue modified peptide carrying a C-terminal amide, D-amino acid residues, and non-standard side chains (norleucine, D-2-naphthylalanine) that are not visible in the raw sequence. Binding affinity at the human delta-opioid receptor was measured at Ki = 3.7 nM (Lee and colleagues, Bioorg Med Chem Lett, 2010).

History

The compound emerged from a research programme led by Victor J. Hruby and colleagues at the University of Arizona, aimed at a recognised limitation of opioid-based analgesia: chronic and neuropathic pain involves dysregulation across multiple receptor systems, not only opioid receptors. The group's earlier work had established that co-administering opioid agonists with antagonists of cholecystokinin (CCK) or melanocortin (MC) receptors enhanced morphine's analgesic potency. The logical extension — encoding all three pharmacophores within a single molecule — produced the trivalent ligand series reported by Lee and colleagues in 2010 (Bioorg Med Chem Lett, 20:4080–4084). CHEMBL1172428 corresponds to compound 11 from that series and is catalogued in ChEMBL with its full bioactivity profile across all five receptor targets tested.

What it does

The compound acts at two opioid receptor subtypes: the human delta-opioid receptor (Ki = 3.7 nM) and the rat mu-opioid receptor (Ki = 4.9 nM), with functional agonist activity confirmed in isolated tissue preparations — mouse vas deferens for the delta receptor (IC50 = 110 nM) and guinea pig ileum for the mu receptor (IC50 = 66 nM). It also binds the CCK-A (CCK-1) receptor with sub-nanomolar affinity (IC50 = 0.79 nM) and more weakly engages the CCK-B (CCK-2) receptor (Ki = 180 nM) and the melanocortin MC4 receptor (IC50 ≈ 500 nM). All bioactivity values are from Lee and colleagues (Bioorg Med Chem Lett, 2010) as reported in ChEMBL (CHEMBL1172428).

The intent behind this receptor profile is pharmacological synergy: delta-opioid agonism suppresses pain signalling in the spinal dorsal horn and peripheral sensory neurons, while CCK-A antagonism counters the anti-opioid effects that cholecystokinin exerts during opioid exposure. The melanocortin MC4 engagement adds a third modulatory layer. Lee and colleagues identified compound 10 of the same series (carrying a dimethyltyrosine N-terminal modification) as the lead, achieving sub-nanomolar affinity at both opioid receptors; CHEMBL1172428 (compound 11) differs primarily in opioid-region substitution pattern and shows a more selective CCK-A profile (Lee and colleagues, 2010).

Evidence

• Human: No human trials. This is a research tool compound characterised in binding and functional assays only.
• Animal: Functional inhibitory activity confirmed in isolated guinea pig ileum (mu-opioid agonist, IC50 = 66 nM) and mouse vas deferens (delta-opioid agonist, IC50 = 110 nM) (Lee and colleagues, 2010). No in vivo rodent efficacy data are available in the public record for this specific compound.
• In vitro: Radioligand displacement at human delta-opioid receptor (Ki = 3.7 nM), rat mu-opioid receptor (Ki = 4.9 nM), human CCK-A receptor (IC50 = 0.79 nM), human CCK-B receptor (Ki = 180 nM), and human MC4 receptor (IC50 ≈ 500 nM) (Lee and colleagues, Bioorg Med Chem Lett, 2010; ChEMBL CHEMBL1172428).

Known effects

• Delta-opioid receptor binding — In vitro; Ki = 3.7 nM (human receptor; Lee and colleagues, 2010)
• Mu-opioid receptor binding — In vitro; Ki = 4.9 nM (rat receptor; Lee and colleagues, 2010)
• CCK-A receptor binding — In vitro; IC50 = 0.79 nM (human receptor; Lee and colleagues, 2010)
• CCK-B receptor binding — In vitro; Ki = 180 nM (human receptor; Lee and colleagues, 2010)
• MC4 receptor engagement — In vitro; IC50 ≈ 500 nM (human receptor; Lee and colleagues, 2010)

Mechanism

The delta-opioid receptor is a seven-transmembrane G protein–coupled receptor (GPCR). Its principal endogenous ligands are the enkephalin neuropeptides, released at synapses in the spinal cord dorsal horn, dorsal root ganglia, and limbic system. DOR activation suppresses pain transmission by reducing neuronal excitability through Gᵢ/Gₒ coupling.

CHEMBL1172428 was designed around two recognised interactions. First, its opioid pharmacophore (incorporating a Tyr-based N-terminal motif and D-amino acid substitutions to resist peptidase degradation) targets the orthosteric binding site shared by endogenous enkephalins. Second, its CCK pharmacophore — derived from a known CCK-A receptor ligand scaffold — addresses the anti-opioid role of cholecystokinin: CCK is co-released in the spinal cord during opioid exposure and functionally dampens opioid receptor signalling. Blocking CCK-A with concurrent opioid agonism was the rationale for both the earlier bifunctional series and the trivalent extension reported in Lee and colleagues (2010). The MC4 pharmacophore segment was appended to test whether melanocortin receptor modulation could be incorporated without loss of activity at the two primary targets.

The solid-phase synthesis used Rink-amide resin under microwave assistance, yielding a C-terminal amide that protects the compound from carboxypeptidase cleavage — an important stability feature for peptide-based research compounds (Lee and colleagues, 2010).

Regulatory status

• Research use only. No IND application, clinical development, or regulatory approval at any agency.
• No registered trials on ClinicalTrials.gov for CHEMBL1172428 or the sequence FHRWDF.

Related peptides

CHEMBL1172428 belongs to a series of multi-target opioid/CCK ligands developed at the University of Arizona. The broader design concept — combining opioid agonism with CCK antagonism in one molecule — spans both bifunctional and trivalent series from the Hruby group. See also other delta-opioid receptor compounds on this platform for comparative DOR binding data.