Peptides›Cognitive›Substance P

Substance P

/ Endogenous undecapeptide; tachykinin family; NK1 receptor agonist

TIER 3 · PreclinicalN = 0 · TESTING PENDINGMW 1347.00 g·mol⁻¹

ALIAS · SP · Neurokinin 1 ligand (endogenous)

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Research use onlyAny dose figures below describe what specific cited studies used, reported factually. Nothing on this page is guidance for human use.READ FIRST →

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§ A · Identity

Primary sequenceRPKPQQFFGLM-NH2

MW · 1347.00CLASS · Endogenous undecapeptide; tachykinin family; NK1 receptor agonistCATEGORY · Cognitive

Tier 3. Foundational sensory-neuroscience peptide first isolated by von Euler and Gaddum in 1931 and sequenced by Chang and Leeman in 1971. Native substance P is not itself a therapeutic; the clinical translation runs through NK1-receptor antagonists (aprepitant, fosaprepitant, rolapitant, netupitant) approved for chemotherapy-induced and post-operative nausea and vomiting.

§ B · Mechanism of action

Substance P is an 11-residue tachykinin synthesised from the preprotachykinin A (TAC1) gene and released from primary afferent C-fibre terminals, enteric neurons, and several CNS nuclei. It binds the neurokinin-1 (NK1) G-protein-coupled receptor with high affinity, and the closely related NK2 and NK3 receptors with lower affinity, signalling principally through Gq/11 to phospholipase C, IP3, and intracellular calcium release.

Functionally, substance P is a co-transmitter in nociceptive signalling at the dorsal horn of the spinal cord, a vasodilator and plasma-extravasation mediator in neurogenic inflammation, and a regulator of emesis acting at the area postrema and nucleus tractus solitarius. The emesis pathway is the basis for clinical translation: NK1 antagonists block central substance P signalling at brainstem vomiting centres.

Native substance P itself is not used therapeutically. Its role in the literature is as a reference ligand for receptor pharmacology and as the endogenous agonist whose blockade defines the NK1-antagonist drug class.

§ C · Human clinical evidence

No development of native substance P as a therapeutic. The clinical evidence base sits with the NK1-antagonist class (aprepitant FDA-approved 2003 for chemotherapy-induced nausea and vomiting; subsequent class members for post-operative nausea). Substance P itself appears in human pharmacology only as an experimental probe for capsaicin-related nociception or microvascular reactivity.

§ D · Primary literature

PubMed7682720Otsuka M et al. — Neurotransmitter functions of mammalian tachykinins · Physiological Reviews · reviewComprehensive review of tachykinin neurotransmitter biology covering substance P, neurokinin A, and neurokinin B; receptor pharmacology and functional roles in nociception, neurogenic inflammation, and CNS signalling.Limitations: Narrative review; predates the NK1-antagonist drug-class clinical era.1993

PubMed14559886Hesketh PJ et al. — The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin · Journal of Clinical Oncology · human-phase-3-rctAprepitant added to standard ondansetron-plus-dexamethasone significantly improved complete response (no emesis, no rescue) in cisplatin chemotherapy; pivotal trial supporting first NK1-antagonist FDA approval.Limitations: Demonstrates clinical translation of the NK1 pathway via receptor antagonism, not native substance P agonism.2003

§ F · Safety signal

Intradermal substance P produces flare and wheal through neurogenic inflammation. Systemic infusion in research settings produces hypotension and flushing; no chronic-administration human safety database exists for the native peptide.

§ H · Regulatory status

Regulatory status

FDA status:: Not FDA-approved

§ I · Notable gaps and controversies

Vendor-sold 'substance P' material is intended for research use, not as a therapeutic. Buyers should be aware that the FDA-approved drugs in this pathway are NK1 antagonists (aprepitant and class members), not the native agonist.

Substance P had a long history of investigation as a depression target after preclinical and small Phase 2 signals; subsequent NK1-antagonist trials in major depressive disorder failed to replicate, and the depression indication was abandoned across multiple sponsors.