Peptides›Cognitive›Neuropeptide Y

Neuropeptide Y

/ Endogenous 36-residue hypothalamic neuropeptide; pancreatic polypeptide family; Y1-Y5 receptor agonist

TIER 3 · PreclinicalN = 0 · TESTING PENDINGMW 4254.00 g·mol⁻¹

ALIAS · NPY

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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 sequenceYPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRY-NH2

MW · 4254.00CLASS · Endogenous 36-residue hypothalamic neuropeptide; pancreatic polypeptide family; Y1-Y5 receptor agonistCATEGORY · Cognitive

Tier 3. Foundational appetite-regulating neuropeptide isolated by Tatemoto in 1982. NPY Y1-receptor antagonists were developed for obesity but did not reach approval; Y2 and Y5 ligands have been explored for various indications including epilepsy and PTSD. No NPY-pathway therapeutic is currently FDA-approved.

§ B · Mechanism of action

Neuropeptide Y is a 36-residue C-terminally amidated peptide of the pancreatic polypeptide family (alongside PYY and PP). It is one of the most abundant peptides in the mammalian central nervous system, with particularly dense expression in the arcuate nucleus of the hypothalamus, where NPY/AgRP co-expressing neurons are a primary orexigenic driver. Peripheral NPY is co-released from sympathetic nerve terminals with norepinephrine.

NPY signals through five GPCRs (Y1, Y2, Y4, Y5, and Y6 in some species), each with distinct pharmacology and tissue distribution. Y1 mediates much of the orexigenic effect at the hypothalamic paraventricular nucleus and the vasoconstrictor effect in peripheral vasculature; Y2 is presynaptic and largely inhibitory, mediating PYY3-36 satiety signalling; Y5 also contributes to feeding regulation.

Beyond appetite, NPY modulates anxiety and stress responses (amygdala Y1 signalling), seizure susceptibility (hippocampal Y2/Y5), circadian entrainment, and cardiovascular tone. The breadth of receptor pharmacology has driven therapeutic interest across obesity, anxiety, PTSD, epilepsy, and neuropathic pain.

§ C · Human clinical evidence

No FDA approvals for NPY or NPY-receptor ligands. Y1-antagonist obesity programs at multiple sponsors did not reach approval. Intranasal NPY has been investigated in small Phase 2 trials for PTSD with preliminary signals but no pivotal trial. Anti-epileptic and neuropathic-pain programs remain preclinical or early clinical.

§ D · Primary literature

PubMed6896083Tatemoto K et al. — Neuropeptide Y - a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide · Nature · in-vitroOriginal isolation and sequencing of NPY from porcine brain; established the pancreatic polypeptide family relationship and the C-terminal amide structure required for receptor binding.Limitations: Discovery paper; no clinical data.1982

PubMed3858854Stanley BG et al. — Neuropeptide Y injected in the paraventricular hypothalamus: a powerful stimulant of feeding behavior · Proceedings of the National Academy of Sciences USA · rodentMicroinjection of NPY into rat paraventricular hypothalamus produced robust dose-dependent feeding behaviour; foundational pharmacological demonstration of central NPY orexigenic action.Limitations: Rodent study; central injection - not transferable to systemic peptide pharmacology.1985

§ F · Safety signal

Acute intravenous NPY produces vasoconstriction and modest blood-pressure elevation. Intranasal NPY in small human studies has been well tolerated short-term. No long-term safety database exists.

§ H · Regulatory status

Regulatory status

FDA status:: Not FDA-approved

§ I · Notable gaps and controversies

The NPY system illustrates the gap between target validation and drug approval - decades of preclinical work establishing receptor pharmacology and physiological function have not produced an approved drug, in part because Y1-antagonist obesity programs ran into selectivity and CNS-penetration challenges.

Vendor-sold NPY peptide is intended for research use. The molecule has no characterised pharmacokinetic profile in humans for self-administration, and peripheral NPY has substantial cardiovascular activity that limits the safety margin for uncontrolled dosing.