Gut & airway nerve-signal blocker (CHEMBL2369631)

What this is

CHEMBL2369631 is a 13-residue synthetic peptide that binds the neurokinin 2 (NK2) receptor, a G protein-coupled receptor found mainly in the smooth muscle of the gut, airways, and urinary tract. It was designed as part of a medicinal chemistry program at the University of Pennsylvania that explored whether a somatostatin-like scaffold could be repurposed to block substance P signalling — specifically at the NK1 and NK2 receptors that tachykinin neuropeptides activate (Liu and colleagues, J Med Chem 2000).

What it does

The peptide binds the NK2 receptor (encoded by the gene TACR2) and inhibits signalling driven by the receptor's preferred endogenous agonist, neurokinin A. Neurokinin A activates NK2 via the Gq/G11 pathway, triggering phospholipase C, inositol trisphosphate release, and a rise in intracellular calcium — the cascade that contracts smooth muscle in the gut and airways. By occupying the receptor, this class of antagonist can dampen that contraction response. The measured affinity for TACR2 is IC50 = 850 nM (ChEMBL assay CHEMBL2369631), placing it in the low-micromolar range characteristic of early-stage research tools rather than optimised drug candidates.

History

The peptide emerged from a programme by Amos Smith III, Ralph Hirschmann, and colleagues at the University of Pennsylvania who were exploring a structurally unusual approach: grafting the pharmacophore of substance P onto a bicyclic somatostatin-like scaffold. Somatostatin and substance P are chemically unrelated neuropeptides, but the Smith–Hirschmann group demonstrated that a β-D-glucose scaffold exhibits "pseudosymmetry" — the same core structure can present different side chains to engage distinct receptors. Building on earlier work showing that glucose-scaffolded peptidomimetics could bind both somatostatin receptors and the NK1 receptor, Liu and colleagues (2000) extended the approach to produce antagonists active at tachykinin receptors including NK2. The NK2 receptor itself had been cloned by Nakanishi's group from a bovine stomach cDNA library — it was in fact the first tachykinin receptor to be cloned — with expression screening in Xenopus oocytes confirming neurokinin A as its preferred ligand.

Evidence

• Human: No human studies for this specific compound. NK2 receptor antagonists as a class have been evaluated in Phase II–III clinical trials for irritable bowel syndrome, asthma, and depression, but none has reached approval; saredutant failed Phase III for depression/anxiety and ibodutant failed Phase III for IBS (Jung and Priefer, Auton Neurosci 2021).
• In vitro: Radioligand binding at TACR2 (human NK2 receptor) in CHO or COS cell systems: IC50 = 850 nM (ChEMBL). The parent programme demonstrated that scaffolded compounds of this series could modulate both NK1 and NK2 receptors depending on substitution pattern, with selectivity controlled by specific side-chain modifications (Liu and colleagues, J Med Chem 2000).

Known effects

• TACR2 (NK2) binding — In vitro, IC50 = 850 nM (ChEMBL bioassay)
• Class effect: bronchoconstriction inhibition — NK2 antagonists as a class block neurokinin A-induced airway smooth muscle contraction; preclinical only for this compound
• Class effect: GI motility modulation — NK2 antagonism reduces NKA-driven intestinal smooth muscle contraction in animal models; not established for this specific compound

Mechanism

TACR2 (NK2R) is a Gq/G11-coupled GPCR that preferentially binds neurokinin A, with lower affinity for substance P and neurokinin B. Upon agonist binding, the receptor activates phospholipase C, generating inositol trisphosphate and diacylglycerol, releasing intracellular calcium stores and activating protein kinase C. This cascade underlies smooth muscle contraction in bronchial, intestinal, and urinary tissues. CHEMBL2369631 was designed to occupy the receptor orthosteric site and suppress this pathway. Its scaffold differs from conventional linear peptide antagonists: the 13-residue sequence was engineered to mimic the β-turn geometry of somatostatin while presenting NK-receptor-targeting side chains — a structural strategy the Smith–Hirschmann group termed pseudosymmetry-based peptidomimetics (Liu and colleagues, J Med Chem 2000). The raw sequence GACKNFFWKTFTS represents a standard amino acid approximation; the specific substitution pattern and any non-standard residues in the active compound are detailed in the primary reference.

Open questions

• Selectivity profile across NK1, NK2, and NK3 receptors for this specific compound is not established in the available literature
• Proteolytic stability and pharmacokinetic properties have not been reported
• Whether the somatostatin scaffold confers simultaneous SRIF receptor affinity alongside TACR2 activity has not been confirmed for this 13-mer specifically
• No in vivo efficacy or safety data exist for this compound