Blood-vessel-narrowing receptor blocker (CHEMBL319719)

What this is

This card is a research-stage peptide ligand of the endothelin-A receptor (EDNRA), reported in the 1995 Journal of Medicinal Chemistry structure–activity study by Cody and colleagues on the dual endothelinA/B antagonist PD 142893. It is not a drug — it is one of dozens of analogs that medicinal chemists made to map which residues at the C-terminus of endothelin-1 actually matter for receptor binding. The stored sequence shown above (LAIIW, five residues) is the standard-amino-acid backbone; the full reported compound is N-terminally acetylated and carries a non-standard β,β-diphenyl-D-alanine (DDip) residue ahead of the leucine, neither of which is encoded by single-letter codes (Cody 1995).

History

The C-terminal hexapeptide of endothelin-1 — His16-Leu-Asp-Ile-Ile-Trp21 — was identified in the early 1990s as the minimum fragment of the 21-residue endothelin peptide that retained antagonist activity at endothelin receptors, making it the starting point for an entire generation of peptide endothelin antagonists. Cody and colleagues at Parke-Davis converted that fragment into PD 142893 (Ac-DDip-Leu-Asp-Ile-Ile-Trp) — one of the first potent peptide antagonists with nanomolar affinity at both endothelinA (ETA) and endothelinB (ETB) receptors — and then walked single-residue substitutions through every position to ask which side chains the receptors actually read (Cody 1995). The card peptide is one of those analogs: it keeps the PD 142893 scaffold but replaces the Asp at position 3 with Ala, so its activity reports on what removing that aspartate carboxylate does.

What it does

In the original receptor-binding assays it behaves as an endothelin receptor antagonist — it sits in the binding pocket and blocks endothelin-1 from activating its receptor, rather than triggering signaling itself. Endothelin-1 is one of the most potent vasoconstrictor peptides known and drives smooth-muscle contraction in blood vessels; antagonists of its receptors relax that signal. The compound binds both endothelin receptor subtypes (ETA and ETB) at nanomolar concentrations and also blocks endothelin-1-stimulated arachidonic acid release in vascular smooth muscle cells (Cody 1995).

Evidence

• In vitro: ETA binding IC50 = 35 nM (rabbit renal vascular smooth muscle membranes); ETB binding IC50 = 16 nM (rat cerebellar membranes); inhibition of endothelin-1-stimulated arachidonic acid release IC50 = 70 nM (rabbit renal vascular smooth muscle cells) (ChEMBL CHEMBL319719, source: Cody 1995, J Med Chem).
• Animal: No in vivo activity reported in the source publication for this specific analog. The parent compound PD 142893 has been characterized in animal models of vasoconstriction by other groups.
• Human: No human studies. This is a tool compound from a medicinal-chemistry SAR series, not a clinical candidate.

Mechanism

The compound is a synthetic analog of the C-terminal pharmacophore of endothelin-1. Endothelin-1 binds its two G-protein-coupled receptors, ETA and ETB, primarily through the hydrophobic C-terminal residues (Ile19, Ile20, Trp21) plus aromatic Phe14 and acidic Asp18 — that region drives recognition, while the disulfide-constrained N-terminal loop fine-tunes affinity (Okuta and colleagues, Communications Biology 2019, on the ETB crystal structure with peptide inverse agonist IRL2500). Hexapeptide antagonists like PD 142893 reproduce just the C-terminal motif and occupy the same pocket, but lack the agonist-promoting interactions and so block rather than activate. The N-terminal acetyl cap and the β,β-diphenyl-D-alanine residue at position 16 (replacing His16 of native endothelin-1) protect against aminopeptidase clipping and add hydrophobic bulk into a subpocket; neither is represented in the stored single-letter sequence. The Asp-to-Ala substitution at the Asp18-equivalent position in this analog tests whether the aspartate carboxylate contributes to receptor engagement (Cody 1995).

Regulatory status

Not a regulated therapeutic. Endothelin receptor antagonism is a clinically validated mechanism — small-molecule dual ETA/ETB antagonists (bosentan, macitentan) and an ETA-selective antagonist (ambrisentan) are FDA- and EMA-approved for pulmonary arterial hypertension (Galiè and colleagues; macitentan SERAPHIN trial, NEJM 2013) — but this peptide compound itself has no regulatory status. It is a research ligand listed in ChEMBL (CHEMBL319719) for academic use.

Related peptides

This compound sits in the C-terminal endothelin hexapeptide antagonist series alongside its parent PD 142893 (Ac-DDip-Leu-Asp-Ile-Ile-Trp) and other single-residue analogs from the same Cody 1995 paper. The mechanism (endothelin receptor antagonism) is shared with the clinically approved small-molecule drugs bosentan, ambrisentan, and macitentan, although those are not peptides. The natural ligand it antagonizes is endothelin-1, a 21-residue disulfide-bridged peptide hormone produced by vascular endothelial cells.