Morphine-receptor-binding research peptide (CYRTT / CHEMBL1795717)

What this is

CHEMBL1795717 is a five-residue research peptide (sequence CYRTT) that binds the μ-opioid receptor — the same receptor targeted by morphine, fentanyl, and most clinical opioid analgesics. It is not a drug. It is a laboratory ligand catalogued in the ChEMBL bioactivity database, drawn from the structure–activity series of CTAP-type somatostatin-template μ-opioid antagonists developed by Victor Hruby's group at the University of Arizona (Kazmierski 1988; Bonner 2000). The reported binding affinity is sub-nanomolar (Ki = 1.06 nM at OPRM1), which is why it appears in receptor-pharmacology screens, but the compound itself has no clinical use and no registered trials.

History

The lineage traces to the late 1980s, when Kazmierski and colleagues at Arizona (1988) re-purposed the conformationally constrained somatostatin octapeptide scaffold — Phe-D-Trp-Lys-Thr in a disulfide-bridged ring — as a template for highly selective μ-opioid receptor antagonists. That work produced CTP (D-Phe-c[Cys-Tyr-D-Trp-Lys-Thr-Pen]-Thr-NH₂) and, through residue substitutions intended to suppress residual somatostatin-receptor binding, the better-known CTAP (Arg in place of Lys) and CTOP (Orn in place of Lys). Bonner and colleagues (2000) extended this with a topographical structure–activity study of the aromatic pharmacophore in CTAP analogues, mapping how β-methyl-Phe and β-methyl-Trp stereoisomers at position 1 shifted compounds between μ-antagonism, δ-agonism, and mixed profiles. CHEMBL1795717 is one entry from this broader CTAP-template SAR space, retained in ChEMBL as a binding-assay reference compound.

What it does

In radioligand-displacement assays, this peptide binds OPRM1 (the μ-opioid receptor) with high affinity (Ki = 1.06 nM, ChEMBL CHEMBL1795717). The μ-opioid receptor is a Gαi-coupled G-protein-coupled receptor whose activation by endogenous opioid peptides (β-endorphin, endomorphins) and exogenous opiates produces analgesia, sedation, respiratory depression, and reward (Pasternak, in Majumdar 2011, references the broader μ-opioid literature). The CTAP-template peptides this compound derives from were specifically engineered to occupy the μ-opioid binding pocket without triggering downstream G-protein signaling — that is, as antagonists rather than agonists (Kazmierski 1988). Functional classification of CHEMBL1795717 itself (agonist, antagonist, partial agonist) is not specified beyond the binding number in the dossier sources, so no functional claim is made here.

Mechanism

The μ-opioid receptor (gene OPRM1, chromosome 6q25) is a class A rhodopsin-like GPCR. Native μ-opioid agonists engage an extracellular orthosteric pocket framed by transmembrane helices and the second extracellular loop; ligand binding reorganises the seven-transmembrane bundle to expose a cytoplasmic Gαi-coupling surface, inhibiting adenylyl cyclase and modulating downstream ion channels. The CTAP-template antagonists (Kazmierski 1988; Bonner 2000) exploit a β-turn-stabilising disulfide between Cys and penicillamine (Pen, a β,β-dimethyl-cysteine), positioning the Tyr and D-Trp side chains as the "message-address" aromatic pharmacophore that engages the μ-receptor binding pocket. The raw stored 5-letter sequence CYRTT (Cys-Tyr-Arg-Thr-Thr) corresponds to the inner residues of that CTAP-family scaffold; published CTAP-series compounds typically include a C-terminal amide and a Cys/Pen disulfide cyclisation that are not encoded in plain one-letter sequence notation. The exact chemistry of CHEMBL1795717's terminal groups and cyclisation state is recorded in the ChEMBL entry rather than in the dossier sources here.

Evidence

• Human: No human studies. CHEMBL1795717 is a research ligand with no clinical investigation.
• Animal: No animal data are attached to this specific ChEMBL entry in the dossier. Related CTAP-template peptides have been characterised in mouse and rat antinociception and locus coeruleus assays in the broader Hruby/Porreca literature (Kazmierski 1988).
• In vitro: Ki = 1.06 nM at the human μ-opioid receptor (OPRM1), per ChEMBL CHEMBL1795717. Methodologically related radioligand-binding assays in the CTAP series are described by Bonner and colleagues (2000); site-selective iodination strategies for opioid radioligand generation are described by Majumdar and colleagues (2011).

Regulatory status

• US: Not a drug, not FDA-regulated as a therapeutic. Research-use chemical only.
• EU: Not an EMA-approved product.
• WADA: Not listed as a named substance. As a μ-opioid receptor ligand, structurally related agonists fall under S7 (Narcotics) in WADA's Prohibited List; this compound has not been characterised as an agonist in the dossier sources, and no WADA listing applies to the research peptide itself.
• ChEMBL: Catalogued as CHEMBL1795717.

Related peptides

• Endomorphin-1 and endomorphin-2 — endogenous μ-selective tetrapeptide agonists; the natural ligands of the receptor that CHEMBL1795717 binds.
• CTAP, CTOP, and other entries in the somatostatin-template μ-opioid SAR series share the Cys-Tyr-X-Thr-Pen disulfide-bridged scaffold described by Kazmierski (1988) and refined by Bonner (2000).