Blood-vessel-relaxing research peptide (CHEMBL85341)

What this is

CHEMBL85341 is a small synthetic peptide developed in the early 1990s as a research tool for blocking the endothelin A receptor (EDNRA) — the receptor that endothelin-1, the body's most potent natural vasoconstrictor, uses to make blood vessels contract. It is a hexapeptide derived from the C-terminal tail of endothelin-1 itself. The card's stored 5-letter sequence (LDIIW) is the bare-residue tail; the actual compound is N-acetyl-D-Tyr-Leu-Asp-Ile-Ile-Trp (Ac-D-Tyr-LDIIW), with an N-terminal acetyl cap and a D-tyrosine at the first position that together flip the parent fragment from a weak agonist into a competitive antagonist. It is a laboratory ligand only and has never been developed as a drug.

History

The compound belongs to the first series of peptide endothelin antagonists, designed at Parke-Davis by Wayne Cody, Annette Doherty and colleagues. Their 1992 paper (Cody et al., J Med Chem 1992) showed that the C-terminal hexapeptide of endothelin-1 — His16-Leu-Asp-Ile-Ile-Trp21 — retains the binding pharmacophore of the parent 21-residue hormone, and that replacing the N-terminal His16 with an N-acetylated D-aromatic amino acid converts the fragment from an agonist into an antagonist. A follow-up SAR study (Doherty et al., J Med Chem 1993) systematically varied the position-16 substituent across a large set of aromatic D-amino acids, mapping the affinity gains that culminated in the more potent PD-series antagonists (PD 142893, PD 145065 and the N-methylated, protease-stable PD 156252; Doherty et al., J Med Chem 1997). CHEMBL85341 sits at the early end of that lineage — a prototype hexapeptide rather than an optimized lead.

What it does

Endothelin-1 (ET-1) is a 21-residue peptide hormone released by vascular endothelial cells; through EDNRA on vascular smooth muscle it triggers strong, sustained vasoconstriction and cell proliferation via the Gq/11 → phospholipase C → IP3/Ca²⁺ pathway (UniProt P25101). CHEMBL85341 mimics only the C-terminal binding tail of ET-1 and occupies the same receptor pocket, but the D-Tyr acetyl cap at position 16 prevents the conformational change needed for receptor activation — so it competes for the binding site without firing it. The result is competitive antagonism of ET-1-evoked signalling at EDNRA in receptor-binding assays.

Evidence

• In vitro: ChEMBL annotates CHEMBL85341 with an IC50 of 400 nM at the endothelin A receptor (ChEMBL database entry CHEMBL85341). This places it in the mid-nanomolar range typical for first-generation hexapeptide antagonists in the Cody/Doherty series — substantially weaker than the later optimized PD 156252 and the cyclic pentapeptide BQ-123 lineage (Doherty et al., J Med Chem 1993).
• Animal: No in vivo studies of this specific compound are reported in the dossier sources; in vivo characterization in the same chemical series was performed on the more potent PD 142893 / PD 145065 / PD 156252 analogs rather than on this early hexapeptide.
• Human: No human studies. This is a research tool, not a clinical candidate.

Regulatory status

Not a drug. CHEMBL85341 has no regulatory status in any jurisdiction; it appears only as a research ligand in the ChEMBL bioactivity database and in the medicinal-chemistry literature cited above.

Related peptides

Endothelin receptor antagonism is now a small, mature drug class — but its clinical successes are all non-peptide small molecules (bosentan, ambrisentan, macitentan) descended from a separate scaffold series, not from the Cody/Doherty hexapeptides. Within the hexapeptide series itself, CHEMBL85341 is an early prototype; the more potent successors PD 142893 (Ac-D-Dip-Leu-Asp-Ile-Ile-Trp), PD 145065 (Ac-D-Bhg-Leu-Asp-Ile-Ile-Trp) and the N-methylated PD 156252 (Ac-D-Bhg-Leu-Asp-Ile-[NMe]Ile-Trp) were developed by the same Parke-Davis group as combined ETA/ETB antagonists with improved proteolytic stability (Doherty et al., J Med Chem 1997). The parallel cyclic-pentapeptide series produced BQ-123, the prototype ETA-selective tool compound widely used in endothelin pharmacology.