Experimental dual-action pain-relief peptide (CHEMBL389652)

What this is

CHEMBL389652 is a research peptide designed in academic medicinal chemistry, not a drug. It belongs to a series of "bifunctional" ligands developed by the Hruby laboratory at the University of Arizona that were engineered to do two things at once in pain pathways: switch on opioid receptors (which dampen pain) and simultaneously block the neurokinin-1 receptor (NK1, gene name TACR1), the receptor for substance P that amplifies pain and contributes to opioid tolerance (Yamamoto, J. Med. Chem., 2007; Nair, Bioorg. Med. Chem. Lett., 2013). The platform stores the stripped 6-residue core YGFMPL, but the actual ChEMBL compound carries a D-Ala at position 2 and a C-terminal 3,5-bis(trifluoromethyl)benzyl ester on a tryptophan tail — modifications that are essential to its measured potency and that are not visible in the raw 6-letter sequence.

History

The bifunctional opioid-agonist / NK1-antagonist design strategy emerged from work by Victor Hruby and Andrzej Lipkowski in the 2000s, building on the long-recognized co-localization of opioid receptors and NK1 receptors in spinal cord pain-processing circuits and on the observation that chronic opioid use up-regulates substance P / NK1 signaling, which in turn drives tolerance and hyperalgesia (Xiao and colleagues, Transl. Perioper. Pain Med., 2016). Yamamoto and colleagues (J. Med. Chem., 2007) reported the first systematic series of C-terminal-modified octapeptides combining a Tyr-D-Ala-Gly-Phe enkephalin-style opioid pharmacophore at the N-terminus with a 3,5-bis(trifluoromethyl)benzyl ester at the C-terminus to confer NK1 antagonism; CHEMBL389652 is one member of this 2007 series. Yamamoto and colleagues (J. Med. Chem., 2008) subsequently used NMR in micelle environments to study the bound conformations of the same series. Nair and colleagues (Bioorg. Med. Chem. Lett., 2013) later truncated the parent octapeptides looking for shorter analogs with retained dual activity.

What it does

In binding and functional assays the compound interacts with three receptors simultaneously: it binds and activates the delta-opioid receptor and the mu-opioid receptor (the targets of morphine and the endogenous enkephalins), and it binds and blocks the NK1 receptor (the receptor that substance P normally activates to relay pain signals). The biological logic of the design is that opioid receptor activation dampens pain transmission while NK1 blockade prevents the substance-P-driven sensitization that limits opioid effectiveness over time (Yamamoto, J. Med. Chem., 2007).

Mechanism

The N-terminal Tyr-D-Ala-Gly-Phe segment is a recognized opioid receptor pharmacophore derived from the natural enkephalins; the D-alanine at position 2 confers resistance to aminopeptidases and tilts selectivity toward the delta receptor. The C-terminal segment — Met-Pro-Leu-Trp extended with a 3,5-bis(trifluoromethyl)benzyl ester — supplies the lipophilic, electron-poor aromatic group that the NK1 receptor binding pocket recognizes in classical small-molecule NK1 antagonists. This is the "overlapping pharmacophore" concept: a single molecule presenting two distinct receptor-recognition surfaces at opposite ends of one peptide backbone (Yamamoto, J. Med. Chem., 2007; Yamamoto, J. Med. Chem., 2008).

Reported ChEMBL bioactivities for CHEMBL389652, traceable to the 2007 J. Med. Chem. publication and curated in ChEMBL, are: Ki ≈ 0.29 nM at human NK1 (cell-based displacement assay), Ki ≈ 2.8 nM at human delta-opioid receptor, and Ki ≈ 36 nM at rat mu-opioid receptor. The compound's functional EC50 at delta-opioid receptor is ≈ 2.9 nM (Yamamoto, J. Med. Chem., 2007, ChEMBL curated activities).

Evidence

• Human: No clinical trials. CHEMBL389652 is a research-tool molecule from a SAR series and has not been advanced to human studies.
• Animal: In vivo work on the broader bifunctional opioid-agonist / NK1-antagonist series — most notably the parent compound TY005 and its successors — has shown analgesia in acute and neuropathic pain models without producing the classical opioid-tolerance signature, providing the proof-of-concept that justified the SAR series CHEMBL389652 belongs to (Yamamoto, J. Med. Chem., 2007; reviewed by Xiao and colleagues, Transl. Perioper. Pain Med., 2016).
• In vitro: Binding and functional measurements at human NK1, human delta-opioid, and rat mu-opioid receptors as listed in Mechanism, sourced from the 2007 J. Med. Chem. publication via the ChEMBL bioactivity record for CHEMBL389652.

Regulatory status

• US: Not an approved drug. Research compound only.
• EU: Not an approved drug.
• WADA: Not listed by trade or compound name. Opioid agonists in general fall under S7 (narcotics) when administered for pain, but this is a laboratory peptide with no clinical or athletic use.

Related peptides

• Met-enkephalin and Leu-enkephalin — the endogenous opioid pentapeptides whose Tyr-Gly-Gly-Phe-Met/Leu N-terminus inspired the opioid pharmacophore in this series.
• Other entries in the Hruby bifunctional opioid-agonist / NK1-antagonist series carry the same Tyr-D-Ala-Gly-Phe backbone with varied C-terminal NK1-recognition groups.