Blood-vessel-tightening blocker (CHEMBL216082)

What this is

This is a research peptide (ChEMBL ID CHEMBL216082) — an experimental endothelin receptor ligand from a 1990s structure–activity series, not a drug or a supplement. It belongs to a family of short peptide antagonists derived from the C-terminal end of endothelin-1, the body's most potent natural vasoconstrictor. The card sequence (LFIIW) corresponds to the standard-amino-acid portion of an N-acetylated hexapeptide whose N-terminal residue is a non-canonical aromatic amino acid (rendered in ChEMBL as an X-coded residue) and is not represented in the five-letter raw sequence shown here. It was made and tested by medicinal chemists at Parke-Davis (Warner-Lambert) as part of the program that produced the prototype dual ETA/ETB antagonist PD 142893 (Cody et al., J Med Chem 1995).

History

Endothelin-1 was discovered in 1988 as a 21-residue peptide produced by vascular endothelial cells. Within a few years, multiple groups had shown that the C-terminal hexapeptide of endothelin — residues His16-Leu17-Asp18-Ile19-Ile20-Trp21 — is the minimum fragment capable of discriminating between endothelin receptor subtypes (Maggi and colleagues, Eur J Pharmacol 1989). Throughout the early-to-mid 1990s, Cody, Doherty, and colleagues at Parke-Davis systematically modified this hexapeptide, replacing His16 with bulky non-canonical aromatic residues (e.g. β,β-diphenylalanine, "DDip") to generate Ac-DDip-Leu-Asp-Ile-Ile-Trp (PD 142893), a potent combined ETA/ETB antagonist. CHEMBL216082 is one of the analogs from that same SAR campaign — specifically a variant in which Asp18 of the parent hexapeptide has been replaced with phenylalanine (the F in LFIIW) — reported in the 1995 Journal of Medicinal Chemistry paper that defined the series (Cody et al., 1995).

What it does

In test-tube binding experiments, this peptide competes with endothelin-1 for the ETA and ETB receptors — the two G-protein-coupled receptors through which endothelin-1 triggers vasoconstriction and vascular smooth-muscle proliferation. It is a research-grade tool compound: it has only ever been characterized in receptor-binding and isolated-tissue assays. It has not been studied in animals as a therapeutic, has no clinical history, and is not a drug.

Mechanism

The compound is an Ac-X-Leu-Phe-Ile-Ile-Trp hexapeptide built around the C-terminal recognition motif of endothelin-1. Earlier work in the same series had shown that affinity for the endothelin receptors increases when His16 is replaced by a non-canonical aromatic residue (DDip, dBhg, or similar X-type substitutions) and that Asp18-substituted analogs can shift the ETA/ETB selectivity profile (Cody et al., J Med Chem 1995). In the bioassays reported in that paper, CHEMBL216082 binds rat ETB with sub-100 nM affinity while binding ETA in the mid-hundreds-of-nanomolar range — making it ETB-leaning rather than ETA-selective, which is the opposite of the direction needed for the major clinical endothelin receptor antagonists in current cardiovascular use.

Evidence

• Human: No human trials. The compound has never advanced beyond in vitro characterization.
• Animal: No published in-vivo data.
• In vitro: Reported in Cody et al. (J Med Chem 1995) and recorded in ChEMBL (entry CHEMBL216082): binding IC50 ≈ 580 nM at the endothelin-1 (ETA) receptor, IC50 ≈ 33 nM at rat ETB, IC50 > 1,600 nM at human ETB, and a functional IC50 ≈ 840 nM in the ETA-mediated assay used by the authors. The 580 nM ETA binding value is what the card subtitle reports.

Related peptides

This card sits within the C-terminal endothelin hexapeptide antagonist series studied by the Parke-Davis group. The clinically used endothelin receptor antagonists (bosentan, ambrisentan, macitentan), which dominate the pulmonary arterial hypertension treatment landscape today, are small-molecule (non-peptide) compounds and are not represented as peptide cards on this platform.