Opioid receptor research tool (CHEMBL216351)

What this is

CHEMBL216351 is a synthetic research compound designed in the late 1980s at Eisai's Tsukuba Research Laboratories to probe how modifications to the opioid peptide dynorphin A change which opioid receptor it activates. It is a laboratory tool — never developed for clinical use — that binds all three classical opioid receptors (mu, delta, and kappa) with different potencies. The compound was characterised alongside 19 other analogs by Yoshino and colleagues in a 1990 structure-activity study published in the Journal of Medicinal Chemistry.

History

Dynorphin A was first isolated from porcine pituitary extract by Avram Goldstein and colleagues in 1979–1981 and named for its extraordinary potency — dyn from the Greek dynamis (power) (Chavkin, Molecular Pharmacology, 2013). The full 17-residue peptide is a selective kappa opioid receptor agonist, but shorter fragments such as Dynorphin A(1–8) lose much of that kappa selectivity and bind mu and delta receptors more comparably (Chavkin 2013). Researchers at Eisai exploited this pharmacological window in the late 1980s to synthesise modified Dyn(1–8) analogs with the goal of improving potency, metabolic stability, and receptor-subtype discrimination. CHEMBL216351 is one of 20 such analogs reported by Yoshino and colleagues in 1990.

What it does

In laboratory binding assays, CHEMBL216351 inhibits signalling at all three classical opioid receptors. It shows strongest activity at the mu opioid receptor, intermediate activity at the delta receptor, and weakest activity at the kappa receptor. The compound served as a research probe to understand how N-methylation and D-amino acid substitutions in the Dynorphin A(1–8) scaffold alter receptor-binding potency and selectivity. No in vivo or human data have been published for this specific compound.

Evidence

• Human: No human trials or clinical data published.
• Animal: No in vivo studies reported for this specific compound. The broader Yoshino 1990 series used guinea pig ileum (GPI), mouse vas deferens (MVD), and rabbit vas deferens (RVD) bioassays as functional surrogates for mu, delta, and kappa receptor activity, respectively.
• In vitro: IC50 = 11.9 nM at the mu opioid receptor (GPI assay), 25.3 nM at the delta opioid receptor (MVD assay), and 189.0 nM at the kappa opioid receptor (RVD assay), all measured in the Yoshino 1990 study (Yoshino et al., J Med Chem, 1990).

Mechanism

CHEMBL216351 is an analog of Dynorphin A(1–8)-NH₂ carrying four non-natural modifications: N-methylation of the Tyr¹ backbone amide, a D-Phe residue at position 4, N-methylation of the Leu⁵ backbone amide, and a C-terminal amide. The raw sequence stored on this card (GGRRL) represents only a subset of the unmodified central residues; the active compound is an 8-residue peptide with formula C₄₈H₇₇N₁₅O₉ (MW 1008.2 Da). The N-methyl groups at positions 1 and 5 protect susceptible amide bonds from aminopeptidase and endopeptidase cleavage — a strategy demonstrated in the Yoshino 1990 series to improve metabolic stability while preserving receptor engagement. The D-Phe⁴ substitution introduces a conformational constraint that prior dynorphin SAR work established as a key determinant of receptor subtype selectivity (Yoshino et al. 1990). The C-terminal amide protects the peptide C-terminus from carboxypeptidase degradation.

Delta opioid receptors (encoded by Oprd1) are seven-transmembrane G protein-coupled receptors that primarily couple to inhibitory Gαi/o proteins; their endogenous ligands are enkephalin peptides derived from the proenkephalin (PENK) precursor (Pradhan and colleagues, Trends in Pharmacological Sciences, 2011). Kappa selectivity in longer dynorphin fragments depends on basic residues in the C-terminal "address" sequence (Arg⁷, Lys¹¹, Lys¹³), which are absent in the 1–8 truncation; this loss of the address sequence is why the compound shows reduced kappa preference relative to full-length dynorphin A (Chavkin 2013).

Open questions

• Whether the N-methyl and D-amino acid substitutions improve metabolic half-life in plasma has not been reported for CHEMBL216351 specifically.
• Selectivity at delta vs. mu receptors is modest (25.3 nM vs. 11.9 nM); structural modifications that would sharpen delta selectivity in this scaffold remain unexplored in the published literature.
• No functional assays (cAMP, β-arrestin recruitment) have been reported — the bioactivity data describe binding displacement only.