Pentapeptide-18
Pentapeptide-18 is the INCI designation for the enkephalin-analog neuromuscular peptide marketed as Leuphasyl by Lipotec, which reduces expression wrinkles by modulating presynaptic acetylcholine release through opioid receptor binding.
Pentapeptide-18 is the International Nomenclature of Cosmetic Ingredients (INCI) designation for the cosmetic peptide marketed by Lipotec as Leuphasyl. It is a synthetic enkephalin analog that reduces facial muscle contraction by binding to opioid receptors on presynaptic motor nerve terminals, decreasing calcium influx and subsequent acetylcholine release.
Overview
Pentapeptide-18 belongs to the neuromuscular-modulating class of cosmetic peptides, which reduce wrinkle formation by decreasing the intensity of facial muscle contractions that create expression lines. It occupies a unique mechanistic niche: while Argireline (Acetyl Hexapeptide-3) inhibits SNARE complex assembly at the post-synaptic level and SYN-AKE mimics waglerin-1 to block nicotinic acetylcholine receptors, Pentapeptide-18 acts upstream of both, reducing the probability of neurotransmitter release from the presynaptic terminal.
The peptide sequence (Tyr-D-Ala-Gly-Phe-Leu) is modeled on Leu-enkephalin, an endogenous opioid pentapeptide involved in pain modulation and neurotransmitter regulation. The D-alanine substitution at position 2 confers resistance to aminopeptidase degradation, extending the peptide's functional half-life in the dermal environment.
Pentapeptide-18 is listed in the CosIng database (European Commission's database for cosmetic ingredients) and is approved for cosmetic use in the EU, US, and most global markets. It is typically formulated at 3-8% of a commercial solution standardized to specific peptide content.
Mechanism of Action
Pentapeptide-18 binds to delta-opioid receptors (DOR) on the presynaptic membrane of motor neurons innervating facial muscles. This triggers a G-protein-coupled signaling cascade that mimics the inhibitory effect of GABA on neuronal excitability:
- Opioid receptor activation -- the peptide engages DOR with affinity comparable to synthetic enkephalin analogs
- G-protein signaling -- receptor activation couples to Gi/Go proteins, inhibiting adenylyl cyclase
- Potassium channel opening -- increased potassium conductance hyperpolarizes the presynaptic terminal
- Calcium channel inhibition -- reduced voltage-gated calcium channel activity decreases calcium influx
- Reduced vesicle exocytosis -- lower intracellular calcium reduces the probability of acetylcholine vesicle fusion and release
The net result is a presynaptic dampening of neuromuscular transmission that softens muscle contraction intensity without producing complete paralysis. This mechanism is complementary to post-synaptic approaches (Argireline, SNAP-8) and receptor-blocking approaches (SYN-AKE), enabling multi-target formulation strategies.
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Research
Anti-Wrinkle Efficacy
Clinical evaluation of Leuphasyl at 5% concentration applied twice daily for 28 days demonstrated measurable reductions in wrinkle depth in the periorbital region. Profilometric analysis showed mean wrinkle depth reductions of approximately 11-15%, with individual responses varying based on baseline wrinkle severity and skin type.
Synergy with Argireline
The most compelling data for Leuphasyl involves its combination with Argireline. A Lipotec-sponsored study evaluated the combination of Leuphasyl (5%) and Argireline (5%) against each peptide alone. The combination produced additive wrinkle reduction of approximately 24.6% mean wrinkle depth decrease over 28 days, exceeding the individual effects of either peptide. This synergy is attributed to simultaneous inhibition at two different points in the neurotransmitter release pathway -- a presynaptic reduction in release probability (Leuphasyl) combined with postsynaptic interference with vesicle fusion machinery (Argireline).
Enkephalin Receptor Binding
In vitro binding assays confirmed that Leuphasyl engages delta-opioid receptors with affinity comparable to synthetic enkephalin analogs. The D-Ala modification maintains receptor selectivity while improving metabolic stability. Importantly, topical application at cosmetic concentrations does not produce systemic opioid effects, as transdermal absorption is insufficient to achieve pharmacologically relevant plasma levels.
Comparative Neuromuscular Peptides
Leuphasyl is generally considered milder than Argireline in standalone use, with a slower onset but potentially better tolerability. In formulation practice, it is most commonly used as a synergistic partner rather than a standalone active, typically at 2-5% in combination products.
Formulation and Stability
Leuphasyl is supplied as an aqueous solution for incorporation into cosmetic formulations. The peptide is stable at pH 5.0-7.0 and compatible with standard cosmetic emulsion systems. The D-amino acid at position 2 confers improved proteolytic stability compared to all-L peptides, extending shelf life in aqueous formulations. Heat sensitivity requires incorporation below 40C during manufacturing. Leuphasyl is compatible with Argireline in co-formulation, with no stability or solubility conflicts at standard use concentrations.
Synergy with Argireline and SNAP-8
The most compelling clinical data for Pentapeptide-18 involves combination use. Lipotec demonstrated that combining Pentapeptide-18 (5%) with Argireline (5%) produced approximately 24.6% mean wrinkle depth reduction over 28 days -- exceeding the efficacy of either peptide alone. The additive effect is attributed to simultaneous inhibition at two distinct points in the neuromuscular cascade: presynaptic release probability (Pentapeptide-18) and postsynaptic vesicle fusion machinery (Argireline). SNAP-8 (Acetyl Octapeptide-3), an extended Argireline analog, provides similar synergistic potential through the same complementary mechanism.
Standalone Anti-Wrinkle Activity
Clinical evaluation of Pentapeptide-18 at 5% concentration applied twice daily for 28 days showed measurable but modest wrinkle depth reductions of 11-15% in the periorbital region. While effective as a standalone active, the peptide's primary value in formulation is as a synergistic partner that enhances the efficacy of other neuromuscular peptides.
Formulation Considerations
Pentapeptide-18 is supplied as an aqueous solution compatible with standard cosmetic emulsion systems. The peptide is stable at pH 5.0-7.0 and can be co-formulated with Argireline and SNAP-8 without stability conflicts. The D-amino acid substitution provides improved proteolytic stability compared to all-L-amino acid peptides. Heat sensitivity requires incorporation below 40C during manufacturing.
INCI Classification and Regulatory Status
Under INCI nomenclature, Pentapeptide-18 is classified as a skin-conditioning agent. It appears on ingredient labels of finished cosmetic products and is distinct from the trade name Leuphasyl, which refers to the commercial ingredient solution that may contain additional formulation components (preservatives, solubilizers). Regulatory filings in the EU CosIng database and US PCPC Dictionary confirm its cosmetic use authorization.
Safety Profile
Pentapeptide-18 has a well-established safety profile for topical cosmetic use. Despite its opioid receptor binding affinity, topical application at cosmetic concentrations does not produce systemic analgesic, sedative, or other opioid effects -- transdermal absorption is insufficient to achieve pharmacologically relevant plasma levels. Clinical and preclinical testing demonstrates no skin irritation, sensitization, or phototoxicity. The peptide is non-mutagenic in standard genotoxicity assays. Long-term application studies show no tachyphylaxis (tolerance development) or rebound effects upon discontinuation. It is considered safe for daily cosmetic use in all approved markets.
Pharmacokinetic Profile
- Half-life
- Not established (enhanced by D-Ala substitution)
Quick Start
- Route
- Topical
Molecular Structure
- Formula
- C₂₈H₃₇N₅O₇
- Weight
- 710.7 Da
- CAS
- 64963-01-5
- PubChem CID
- 6436230
- Exact Mass
- 710.2786 Da
- LogP
- 0.7
- TPSA
- 245 Ų
- H-Bond Donors
- 6
- H-Bond Acceptors
- 16
- Rotatable Bonds
- 9
- Complexity
- 1490
Identifiers (SMILES, InChI)
InChI=1S/C34H46O16/c1-12(2)13(3)8-19(36)50-24-26-33-11-46-34(26,31(44)45-6)28(42)23(40)25(33)32(5)15(9-18(33)49-29(24)43)14(4)7-16(27(32)41)47-30-22(39)21(38)20(37)17(10-35)48-30/h7-8,12,14-15,17-18,20-26,28,30,35,37-40,42H,9-11H2,1-6H3/b13-8+
YSFALLIAQRJCQF-MDWZMJQESA-NResearch Protocols
topical
Importantly, topical application at cosmetic concentrations does not produce systemic opioid effects, as transdermal absorption is insufficient to achieve pharmacologically relevant plasma levels. Safety Profile Leuphasyl has a favorable safety profile in topical cosmetic applications.
| Goal | Dose | Frequency | Duration |
|---|---|---|---|
| General Research Protocol | See literature | Daily | —(Route: Topical) |
transdermal Injection
Despite its opioid receptor binding affinity, topical application at cosmetic concentrations does not produce systemic analgesic, sedative, or other opioid effects -- transdermal absorption is insufficient to achieve pharmacologically relevant plasma levels.
| Goal | Dose | Frequency | Duration |
|---|---|---|---|
| General Research Protocol | See literature | Daily | —(Route: Topical, Transdermal) |
Interactions
Peptide Interactions
The most compelling data for Leuphasyl involves its combination with Argireline. A Lipotec-sponsored study evaluated the combination of Leuphasyl (5%) and Argireline (5%) against each peptide alone. The combination produced additive wrinkle reduction of approximately 24.6% mean wrinkle depth decr...
This mechanism is complementary to post-synaptic approaches (Argireline, SNAP-8) and receptor-blocking approaches (SYN-AKE), enabling multi-target formulation strategies.
Quality Indicators
What to look for
- Well-established safety profile
Frequently Asked Questions
References (6)
- [2]
- [5]
- [6]Negari et al -- Peptide-based cosmeceuticals: an evolving field of investigation Int J Mol Sci (2023)
- [7]Schagen SK -- Cosmeceutical peptides: signal peptides, neurotransmitter inhibitors, carrier peptides J Cosmet Dermatol (2022)
- [1]Blanes-Mira C et al A synthetic hexapeptide (Argireline) with antiwrinkle activity Int J Cosmet Sci (2002)
- [3]Lintner K et al Cosmetic peptides Int J Cosmet Sci (2009)
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