Dynorphin A look-alike: brain's own painkiller peptide (CHEMBL2028997)

What this is

This card describes a 17-amino-acid research peptide catalogued in ChEMBL as CHEMBL2028997. Its sequence is nearly identical to dynorphin A (1-17) — a natural opioid peptide produced in the human brain — but with a single change at the C-terminus: the final glutamine (Q) of natural dynorphin A is replaced by glutamic acid (E), making the stored sequence YGGFLRRIRPKLKWDNE rather than the canonical YGGFLRRIRPKLKWDNQ. The peptide is a laboratory ligand: it was synthesised and characterised in opioid-receptor binding studies in the mid-1980s and revisited in more recent receptor-screening work. It is not a drug, not a supplement, and has no clinical or regulatory status.

History

The peptide appears as a reference compound in Gairin and colleagues (Journal of Medicinal Chemistry, 1986), a synthesis-and-pharmacology paper aimed at developing kappa-selective opioid antagonists by introducing D-amino-acid substitutions into shorter dynorphin A (1-11) fragments. The same compound was later included in receptor-screening work by Lansu and colleagues (Nature Chemical Biology, 2017), which profiled dynorphin-derived peptides against the atypical opioid-binding receptor MRGPRX2 alongside classical opioid receptors. Dynorphin A itself was first isolated from porcine pituitary by Avram Goldstein's group in 1979 — the suffix "dynorphin" reflects its unusually high (dyna-) intrinsic potency at the time of discovery — and the peptide's first thirteen residues correspond to the historical "dynorphin A (1-13)" fragment used in much of the early opioid pharmacology literature.

What it does

Like natural dynorphin A, this peptide binds all three classical opioid receptors — kappa (KOR), mu (MOR) and delta (DOR) — and acts as an agonist at each, with the strongest affinity at the kappa receptor. The first four residues (YGGF, "Tyr-Gly-Gly-Phe") are the conserved opioid "message" motif shared by enkephalins, endorphins and dynorphins; this is the part of the molecule that engages the receptor's orthosteric binding pocket. The basic C-terminal "address" segment (LRRIRPKLKWDNQ in natural dynorphin, LRRIRPKLKWDNE here) is what biases the peptide toward kappa receptors over mu and delta. The platform stores this card under the delta- and mu-receptor targets because both receptors are bound with high affinity; the peptide's strongest target, however, is the kappa receptor.

Mechanism

The opioid receptors KOR, MOR and DOR are Gαi/o-coupled G-protein-coupled receptors. Agonist binding inhibits adenylate cyclase, reduces cyclic AMP, closes voltage-gated calcium channels and opens inwardly rectifying potassium channels — collectively reducing the excitability of the neuron carrying the receptor. The "message-address" model of dynorphin pharmacology, articulated in the early 1980s, partitions the peptide into an N-terminal tetrapeptide responsible for receptor activation and a C-terminal basic extension responsible for receptor selectivity. The Gln→Glu substitution at position 17 in this analog sits at the far end of the address segment and is conservative in size but flips a neutral amide side-chain to an acidic carboxylate, which can be expected to alter local electrostatics at the C-terminal tail without disrupting the message pharmacophore. The receptor-binding data reported in ChEMBL for this peptide is consistent with that expectation — the message-driven core activity at kappa, mu and delta is preserved (Gairin et al. 1986).

Evidence

• In vitro (receptor binding): In rat-brain membrane displacement assays reported in Gairin and colleagues (J Med Chem 1986), the peptide displaced [³H]bremazocine from kappa sites in guinea-pig cerebellum with Ki ≈ 0.23 nM, [³H]DAGO from mu sites in rat brain with Ki ≈ 1.55 nM, and [³H]DSLET from delta sites in rat brain with Ki ≈ 6.3 nM (values catalogued under CHEMBL2028997).
• In vitro (functional bioassays): In isolated-tissue agonist bioassays from the same paper, the peptide inhibited electrically evoked contractions with IC50 ≈ 0.28 nM in guinea-pig ileum (mu-selective preparation), IC50 ≈ 3.07 nM in rabbit vas deferens (kappa-selective preparation), and IC50 ≈ 262 nM in hamster vas deferens (delta-selective preparation) (Gairin et al. 1986).
• In vitro (atypical opioid receptor): Lansu and colleagues (Nature Chemical Biology 2017) profiled dynorphin-derived peptides against the Mas-related G-protein-coupled receptor X2 (MRGPRX2); the compound activated MRGPRX2 in a calcium-mobilisation FLIPR assay with EC50 ≈ 2.45 µM, roughly four orders of magnitude weaker than its activity at the classical opioid receptors.
• Animal / human: No animal-disease or human studies of this specific [Glu17] analog are present in the dossier sources.

Known effects

• Kappa-opioid receptor agonism — Receptor-binding and isolated-tissue evidence (Gairin et al. 1986).
• Mu- and delta-opioid receptor agonism — Receptor-binding and isolated-tissue evidence at lower selectivity (Gairin et al. 1986).
• Weak MRGPRX2 activity — In vitro calcium-mobilisation evidence at micromolar concentrations (Lansu et al. 2017).

Regulatory status

This is a research-only peptide catalogued in ChEMBL. It is not an approved drug, not under clinical investigation, and not listed by FDA, EMA or WADA under its ChEMBL identifier. Natural dynorphin A is an endogenous peptide and is also not a regulated substance.

Related peptides

• Members of the broader endogenous opioid peptide family — including the enkephalins, β-endorphin and the other dynorphins — share the N-terminal YGGF "message" tetrapeptide and signal through KOR, MOR and DOR. Specific platform cards for those peptides are not linked here because their pep-IDs have not been verified for this draft.

peptidemodel.com