Dynorphin-derived opioid research peptide (CHEMBL1790761)

What this is

CHEMBL1790761 is a synthetic research peptide derived from dynorphin A, an endogenous opioid neuropeptide found throughout the brain and spinal cord. It was prepared as part of a medicinal-chemistry campaign aimed at understanding how structural changes to the dynorphin backbone alter binding selectivity across the three main opioid receptor subtypes — kappa, mu, and delta. The compound is a tool molecule used in receptor pharmacology experiments; it has no approved therapeutic use and has never entered clinical trials.

The raw sequence stored for this card (YGFLRRIRK) is a nine-letter standard-letter approximation. The ChEMBL entry (CHEMBL1790761) documents the actual compound as an 11-residue amidated peptide — formally [D-Ile³,D-Pro¹⁰]Dyn A(1-11)-NH₂ — carrying D-isoleucine at position 3, D-proline at position 10, and a C-terminal amide cap, none of which appear in the nine-letter representation. These non-natural modifications substantially affect the peptide's receptor binding and functional profile.

History

Dynorphin A was first isolated from porcine pituitary by Avram Goldstein and colleagues in 1979, and its full 17-residue sequence (YGGFLRRIRPKLKWDNQ) was determined in 1981. Its name combines the Greek dynamis (power) with "orphin" (for endorphin), reflecting its extraordinary potency — later confirmed as approximately 700-fold greater than leucine-enkephalin in bioassays. The N-terminal pentapeptide YGGFL is identical to leucine-enkephalin; the basic C-terminal extension, particularly arginine at position 7 and lysine at positions 11 and 13, drives kappa receptor selectivity.

Truncated fragments such as dynorphin A(1-11)-NH₂ retain full kappa receptor binding and became standard SAR scaffolds. Systematic substitution at positions 2 and 3 was pursued through the 1990s and 2000s to map which residues govern receptor subtype selectivity and functional efficacy. Schlechtingen and colleagues (J Med Chem, 2000) characterised a series of position-3 variants, including this D-Ile³ analogue, measuring their affinities at cloned human opioid receptors in CHO cell membranes (Schlechtingen and colleagues 2000).

What it does

The peptide binds the kappa opioid receptor with a Ki of 55.0 nM, measured in a radioligand competition assay against the cloned human kappa receptor expressed in CHO cell membranes (Schlechtingen and colleagues 2000). Kappa opioid receptors (KOR) are G protein-coupled receptors that modulate pain signalling, stress responses, and mood through inhibition of adenylyl cyclase and downstream cAMP pathways; dynorphin peptides are their principal endogenous ligands.

Despite moderate binding affinity, the D-Ile³ substitution substantially reduces functional agonist activity compared to the parent dynorphin A(1-11)-NH₂ scaffold. Position-3 analogues bearing bulky lipophilic D-amino acids retain measurable receptor occupancy but lose the backbone geometry required for full receptor activation, producing weak or negligible agonism in functional bioassays (Schlechtingen and colleagues 2000). The compound is therefore best described as a low-efficacy ligand at KOR under the conditions studied.

The card target metadata lists OPRD1 (delta opioid receptor); the single bioassay indexed for CHEMBL1790761 in ChEMBL is kappa receptor binding only — no delta receptor measurement is on record for this compound.

Evidence

• Human: No human studies. This compound has been used only as a receptor pharmacology research tool.
• Animal: Not reported for this compound.
• In vitro: Ki = 55.0 nM at the kappa opioid receptor in CHO cell membranes expressing the cloned human receptor (Schlechtingen and colleagues 2000). Functional agonist activity is weak for the D-Ile³ class relative to the parent peptide, consistent with impaired activation geometry at position 3 (Schlechtingen and colleagues 2000).

Mechanism

Dynorphin A-(1-11) analogues bind opioid receptors through a two-domain framework: the N-terminal tetrapeptide Tyr-Gly-Gly-Phe (the "message" sequence shared by all opioid peptides) drives receptor activation, while the C-terminal "address" residues — particularly the arginine-rich stretch at positions 6 and 7 — confer selectivity for kappa over mu and delta receptors by electrostatic contacts with the receptor's extracellular loops.

Position 3 lies within the message sequence and is critical for both affinity and efficacy. Small residues at this position (Ala, D-Ala) preserve both high kappa affinity and agonist potency; bulky lipophilic D-amino acids (D-Ile, as in this compound) retain measurable affinity while eliminating most agonist potency, suggesting position 3 participates in the conformational rearrangement that triggers Gαi/o activation rather than simply in initial receptor docking (Schlechtingen and colleagues 2000). The [Pro³]Dyn A(1-11)-NH₂ analogue, studied in the same series, achieved approximately 3,260-fold selectivity for kappa over delta with a Ki of 2.7 nM at KOR, illustrating how sharply a single position-3 change can alter the pharmacological outcome.

Known effects

• Kappa opioid receptor binding — In vitro, Ki = 55.0 nM at human KOR (Schlechtingen and colleagues 2000)
• Functional kappa agonism — Weak; substantially reduced relative to parent dynorphin A(1-11)-NH₂ (Schlechtingen and colleagues 2000)

Open questions

• No mu or delta opioid receptor binding data have been published for CHEMBL1790761; its full selectivity profile relative to the [Pro³] parent remains uncharacterised.
• Functional classification (partial agonist vs. silent/competitive ligand) has not been formally established.
• Proteolytic stability and plasma half-life have not been reported.
• No in vivo analgesic or behavioural data exist for this specific analogue.