Pain-signaling blocker peptide (YGFGPL)

What this is

YGFGPL (ChEMBL identifier CHEMBL426363) is a synthetic six-residue peptide that binds to the neurokinin-1 receptor (NK1R, also called the substance P receptor or TACR1). It was identified as a compact pharmacophore fragment in the course of research into bifunctional analgesic peptides — compounds designed to simultaneously activate opioid receptors and block the NK1 receptor, a strategy intended to improve pain relief while reducing opioid tolerance. The sequence Tyr-Gly-Phe-Gly-Pro-Leu represents the core N-terminal scaffold used in that work.

History

YGFGPL emerged from a program at the University of Arizona led by Victor Hruby, Frank Porreca, and colleagues, who sought to merge two distinct analgesic mechanisms into a single molecule. Opioid agonists (acting at μ and δ receptors) and NK1 receptor antagonists (blocking the actions of substance P) had each been validated separately for pain, and preclinical work showed that combining them could produce additive or synergistic analgesia with attenuated tolerance. Yamamoto and colleagues (Journal of Medicinal Chemistry, 2007) reported a series of C-terminally modified octapeptides built on the Tyr-Gly-Phe-Gly-Pro-Leu scaffold; compound 3 of that series, which appends Trp with a bulky 3′,5′-bis(trifluoromethyl)benzyl ester to the C-terminus of this hexapeptide core, displayed Ki = 1.0 nM at the rat NK1 receptor alongside potent δ/μ opioid receptor binding. The hexapeptide YGFGPL as a discrete 6-mer entity is catalogued in ChEMBL (CHEMBL426363) with the Ki = 1.0 nM annotation derived from that study.

What it does

YGFGPL acts as a ligand at the neurokinin-1 receptor, the primary receptor for the neuropeptide substance P. Substance P is released in the spinal dorsal horn during painful stimuli, where it amplifies pain signals; blocking the NK1 receptor dampens this amplification. In the context of the bifunctional peptide programme, the Tyr-Gly-Phe-Gly-Pro-Leu scaffold also contributed the enkephalin-like opioid pharmacophore (the Tyr-Gly-Phe motif characteristic of enkephalin N-termini), meaning the same hexapeptide backbone could engage both receptor systems. The rationale, supported by preclinical co-administration studies, was that simultaneous NK1 antagonism and opioid activation in the spinal cord could enhance analgesic efficacy and suppress the tolerance that develops with opioids alone.

Evidence

• Human: No human trials published for YGFGPL or CHEMBL426363 as an isolated compound. No registered trials on ClinicalTrials.gov for this compound.
• Animal: Bifunctional peptides built on this scaffold (including the full octapeptide compound 3) demonstrated antinociceptive activity in rodent pain models as reported by Yamamoto and colleagues (2007) and in subsequent studies from the same programme.
• In vitro: Ki = 1.0 nM at the rat NK1 receptor (TACR1), as recorded in ChEMBL and traceable to Yamamoto and colleagues (Journal of Medicinal Chemistry, 2007).

Known effects

• NK1 receptor binding — In vitro, Ki = 1.0 nM (rat TACR1; ChEMBL/Yamamoto 2007)
• Opioid receptor pharmacophore contribution — The Tyr-Gly-Phe triad at the N-terminus is the classical enkephalin address motif; confirmed in the bifunctional compound series context (Yamamoto and colleagues, 2007)
• NK1 antagonism (functional) — Demonstrated for full bifunctional compounds carrying this scaffold in isolated tissue assays (Yamamoto and colleagues, 2007)

Mechanism

The NK1 receptor (TACR1) is a Gq/11-coupled GPCR whose primary endogenous agonist is substance P. Upon substance P binding, the receptor activates phospholipase C-β, generating IP₃ and diacylglycerol, elevating intracellular calcium and activating protein kinase C; downstream signalling includes MAPK and NF-κB activation. In the spinal dorsal horn, where NK1R and opioid receptors are co-expressed, substance P release during nociception sustains and amplifies the pain signal. The YGFGPL hexapeptide presents two overlapping pharmacophores within one compact sequence: the N-terminal Tyr-Gly-Phe segment mirrors the opioid address motif of Leu-enkephalin, while the Pro-Leu C-terminus contributes to the NK1 antagonist binding geometry seen in substance P-derived inhibitory fragments. In the full bifunctional compounds, the appended C-terminal Trp with a bulky aromatic ester completes the NK1 antagonist pharmacophore, producing subnanomolar NK1 affinity. The YGFGPL scaffold itself captures the core residues common to both pharmacophores, accounting for its high-affinity NK1 binding.

Safety signals

No clinical safety data exist for YGFGPL. It has not entered clinical development as a standalone compound. As a research-stage peptide studied only in vitro and in preclinical models, its safety profile in humans is unknown.

Regulatory status

• US / EU: Not approved. Research compound only.
• ClinicalTrials.gov: No registered trials for CHEMBL426363 or YGFGPL.

Related peptides

The broader bifunctional opioid/NK1 programme produced numerous analogs building on this scaffold. Substance P, the endogenous NK1 agonist, is the 11-residue tachykinin whose C-terminal hexapeptide region informs NK1-active fragment design. Leu-enkephalin and related enkephalin sequences share the Tyr-Gly-Phe opioid address motif present at the N-terminus of YGFGPL.