Sar9, Met (O2)11-Substance P

Summary

Sar9,Met(O2)11‑Substance P is a synthetic analogue of the neuropeptide Substance P that acts as a highly selective agonist of the neurokinin‑1 (NK1) receptor. Developed for research, it is used to probe NK1‑mediated signaling in the central nervous system, respiratory tract, and peripheral tissues. The compound is not approved for therapeutic use and is employed primarily in animal models, isolated tissue preparations, and radioligand binding studies.

Mechanism of Action

The peptide binds the NK1 receptor with sub‑nanomolar affinity (Kd ≈0.1–0.3 nM) and activates the associated G‑protein coupled signaling cascade. Activation leads to intracellular calcium mobilization, smooth‑muscle contraction, and release of inflammatory mediators such as prostanoids. In the brain, NK1 activation influences neurotransmitter release, including modulation of acetylcholine in the neostriatum. The analogue’s structural modifications (Sar at position 9, Met(O2) at position 11) enhance receptor selectivity over NK2 and NK3 subtypes.

What the Research Shows

Binding studies using radiolabelled [125I]‑ and [3H]‑Sar9,Met(O2)11‑SP demonstrated high‑affinity, selective NK1 binding in rat brain, submandibular gland, and guinea‑pig ileum, with Kd values between 0.1 and 2 nM and low nonspecific binding. Autoradiography revealed dense NK1 sites in olfactory bulb, striatum, amygdala, hippocampus, and spinal cord. In vivo, intravenous infusion in conscious guinea‑pigs produced airway obstruction at doses 30‑fold higher than those needed for plasma extravasation, indicating distinct functional outcomes. In human isolated bronchi, interleukin‑1β pretreatment amplified SP‑induced contraction via COX‑2‑derived prostanoids, an effect blocked by cyclooxygenase inhibitors and TP‑receptor antagonists. Developmental studies showed NK1‑mediated excitation of acetylcholine release from rat neostriatal slices as early as post‑natal day 5, independent of dopaminergic lesions. Collectively, these data establish the analogue as a potent tool for mapping NK1 distribution and probing tachykinin‑driven physiological responses.

Reported Benefits

The analogue provides a highly selective probe for NK1 receptors, enabling precise mapping of receptor distribution in brain and peripheral tissues. Its potency allows detection of low‑capacity NK1 sites and dissection of tachykinin‑mediated pathways in airway reactivity, inflammation, and neurodevelopment. The compound’s radiolabelled forms serve as valuable ligands for quantitative binding assays and autoradiography, facilitating drug‑discovery efforts targeting NK1‑related disorders.

Limitations of the Evidence

Evidence is confined to animal experiments, isolated human tissue, and in vitro binding assays; no clinical trials or therapeutic evaluations exist. Species differences in NK1 receptor density and signaling may limit extrapolation to humans. The studies focus on acute administration, leaving chronic effects and pharmacokinetics uncharacterized. Safety data are limited to observed bronchoconstriction and plasma extravasation in rodents, providing an incomplete risk profile for broader use.

Safety Considerations

Acute intravenous dosing in guinea‑pigs produced airway obstruction and pulmonary plasma extravasation, indicating potential respiratory irritation. No systemic toxicity or mortality was reported, but the lack of human safety data precludes definitive conclusions. In vitro human bronchi responded with enhanced contraction after inflammatory priming, suggesting that inflammatory states could amplify adverse bronchial effects. Researchers should monitor respiratory parameters and avoid high doses in sensitive models.

How It Is Administered

In experimental settings Sar9,Met(O2)11‑Substance P is delivered via intracerebral, intrathecal, intradermal, or intravenous routes, depending on the target tissue. Radiolabelled versions are administered in low nanomolar concentrations for binding assays, while functional studies employ bolus or perfusion injections to elicit physiological responses.

Routes of Administration

Goals & Uses

• NK1 receptor activation (research)Pharmacological ToolHigh
• NK1 receptor internalization assaysReceptor BiologyHigh
• NK1 receptor agonismPharmacologyModerate
• Neuroinflammation studiesInflammation ResearchModerate
• Nociception and pain researchNeuroscience ResearchModerate
• Peptide stability studiesFormulationModerate
• Pain pathway investigationResearchModerate

Contraindications

• Severe cardiovascular diseaseCardiovascularModerate
• Human therapeutic useRegulatory/safetyHigh

Adverse Effects

• HypotensionCardiovascularUnknownLow blood pressure
• Nociceptive behavior (hyperalgesia/allodynia)NeurologicalCommon
• BronchoconstrictionRespiratoryUnknown
• Plasma protein extravasation / edemaInflammatoryCommon

Drug Interactions

• NK1 receptor antagonists (e.g., aprepitant, L-703,606)High
• NK1 antagonists (e.g., aprepitant)High

Population Constraints

• General human populationRegulatory/safetyAbsolute
• Pregnant animalsReproductiveRelative

Regulatory Status

• European UnionUnapprovedNot authorized for clinical use.
• United StatesUnapprovedOnly available as a research chemical.
• United KingdomUnapprovedNo MHRA registration; research use only.

Not approved for any therapeutic indication; used solely as a research tool.

Evidence & Sources

• Pulmonary actions of the neurokinin1-specific agonist [Sar9,Met(O2)11]-substance P
  Journal ArticleLowYiamouyiannis CA, et al.1995-01-01T00:00:00.000000Z
• Binding characteristics of [125I]Bolton-Hunter [Sar9,Met(O2)11]substance P, a new selective radioligand for the NK1 receptor
  Journal ArticleLowLew R, et al.1990-01-01T00:00:00.000000Z
• Postnatal development of functional dopamine, opioid and tachykinin receptors that regulate acetylcholine release from rat neostriatal slices. Effect of 6-hydroxydopamine lesion
  Journal ArticleModeratePérez-Navarro E, Alberch J, Marsal J1993-01-01T00:00:00.000000Z
• Autoradiographic distribution of brain neurokinin-1/substance P receptors using a highly selective ligand [3H]-[Sar9,Met(O2)11]-substance P
  Journal ArticleLowDam TV, Martinelli B, Quirion R1990-01-01T00:00:00.000000Z
• Interleukin-1beta-induced hyperresponsiveness to [Sar9,Met(O2)11]substance P in isolated human bronchi
  Journal ArticleLowBarchasz E, et al.1999-01-01T00:00:00.000000Z
• Binding sites for [3H][Sar9, Met(O2)11]substance P in rat brain and guinea pig ileum
  Journal ArticleLowTousignant C, Guillemette G, Regoli D1991-01-01T00:00:00.000000Z

Frequently Asked Questions