Blood-vessel-tightening research peptide (CHEMBL317099)

What this is

This is a six-amino-acid synthetic peptide (Phe-Phe-Asp-Ile-Ile-Trp) catalogued in the ChEMBL chemistry database as CHEMBL317099. It is a laboratory research compound — not a drug, not a clinical candidate — used in the 1990s to map the binding requirements of the endothelin receptors, a pair of receptors (ETA and ETB) that endothelin-1 acts on to constrict blood vessels and regulate vascular tone. The stored six-letter sequence is the bare backbone; the actual research compound is N-terminally acetylated (Ac-Phe-Phe-Asp-Ile-Ile-Trp), and the acetyl cap is what the published bioassays measured. It belongs to a family of short C-terminal endothelin analogs built around the Asp-Ile-Ile-Trp tail that is shared with native endothelin-1 residues 18–21.

History

The endothelin C-terminal hexapeptide framework was developed at Parke-Davis as part of an effort to find short, drug-like blockers of the endothelin receptors. Cody and colleagues at Parke-Davis (J. Med. Chem., 1992) first described a functional hexapeptide endothelin antagonist by replacing the histidine and leucine at positions 16 and 17 of endothelin-1 with unnatural hydrophobic residues, showing that a six-residue fragment could retain receptor binding (Cody 1992). The same group extended this work into a full structure–activity series, identifying Ac-DDip-Leu-Asp-Ile-Ile-Trp (PD 142893) as a low-nanomolar mixed ETA/ETB antagonist and systematically substituting each position to map out what the receptors would tolerate (Cody 1995). The Ac-Phe-Phe-Asp-Ile-Ile-Trp analog in this card is one of the substituted variants from that SAR program, where the unnatural diphenylalanine at position 16 and the leucine at position 17 were both replaced with plain phenylalanine.

What it does

In purified-membrane binding assays, this peptide competes with endothelin-1 for both endothelin receptor subtypes, but it is much more potent at ETB than at ETA. Reported IC50 values from the original SAR paper are 910 nM at the ETA receptor and 20 nM at the ETB receptor (Cody 1995, J. Med. Chem.), making it roughly 45-fold ETB-selective in binding. In a functional cellular readout — inhibition of endothelin-1-stimulated arachidonic acid release in rabbit renal vascular smooth muscle cells — the ETA functional IC50 was 2,100 nM (Cody 1995). It has no reported activity outside this in-vitro receptor-pharmacology context.

Mechanism

The endothelin receptors ETA and ETB are class A G-protein-coupled receptors. ETA (encoded by the EDNRA gene, 427 amino acids in humans) couples primarily to Gq/G11 and signals through phospholipase C, generating IP3 and DAG to mobilize intracellular calcium for vasoconstriction (IUPHAR/BPS Guide to Pharmacology, ETA receptor entry). The C-terminal end of endothelin-1 — the Asp-Ile-Ile-Trp tail at positions 18–21, plus His and Leu at 16–17 — is the part of the natural ligand that sits in the receptor's orthosteric pocket; short peptides that reproduce this tail can occupy that pocket and block endothelin-1 binding without triggering full activation. Recent cryo-EM structures of both endothelin receptors in complex with small-molecule and peptide antagonists show that the C-terminal tail of endothelin-1 makes the deepest contacts in the receptor pocket and that selectivity between ETA and ETB is dictated by a small number of residues lining that pocket (Hou et al., Cell Discovery, 2024). For this peptide, replacing the natural histidine at position 16 with a plain phenylalanine appears to favor ETB binding over ETA — consistent with the broader Parke-Davis SAR finding that the residue at position 16 is a key selectivity switch (Cody 1995).

Evidence

• Human: No human studies. This is a tool compound that exists only in published receptor-binding and tissue-pharmacology assays.
• Animal: Tested in rabbit renal vascular smooth muscle cells as a functional ETA antagonist (Cody 1995). No in-vivo studies reported.
• In vitro: Primary binding data are ETA IC50 = 910 nM and ETB IC50 = 20 nM (Cody 1995; ChEMBL CHEMBL317099 activity record).

Regulatory status

Not a regulated therapeutic. No marketing authorization (FDA, EMA, or other) and no clinical-trial history. The compound exists as a catalogued ChEMBL bioassay entry derived from the 1995 SAR publication. It is not listed by WADA.

Related peptides

The broader endothelin-antagonist program that produced this peptide eventually yielded the orally active small-molecule ETA/ETB and ETA-selective antagonists used clinically today (bosentan, ambrisentan, macitentan, atrasentan, zibotentan), none of which are peptides — the peptide series was an early structural lead, not the final clinical scaffold. Within the platform, no other cards in the FFDIIW SAR series are currently catalogued.