Melanotan II 10mg,
Cyclic α-MSH Analog
A Lactam-Bridged Tool for Melanocortin Receptor Research
Introduction
A Lactam-Bridged Tool for Melanocortin Receptor Research
Melanotan II is a synthetic cyclic peptide analog of α-melanocyte-stimulating hormone (α-MSH). Its lactam-bridged design produces enhanced metabolic stability and high potency across the broader melanocortin receptor family (MC1R through MC5R).
Native α-MSH is a 13-residue linear tridecapeptide rapidly degraded by serum proteases. Melanotan II addresses this limitation through cyclisation: an N-α-aspartic acid and a C-terminal lysine are connected via a lactam bridge, locking the active receptor-binding region into a stable conformation that simultaneously improves enzymatic stability and enhances receptor binding affinity. The result is a compact cyclic peptide with the sequence Ac-Nle-cyclo(Asp-His-D-Phe-Arg-Trp-Lys)-NH2 that retains potent activity across the melanocortin receptor family.
Disclosed by Mac Hadley, Robert Dorr, and colleagues at the University of Arizona in the 1980s as part of a systematic structure-activity programme, Melanotan II became one of the most-cited synthetic α-MSH analogs in melanocortin research. The compound is non-selective across the melanocortin receptor family, with documented activity at MC1R (pigmentation), MC3R and MC4R (appetite and energy balance), MC5R (exocrine function), and MC2R (the ACTH receptor, though with weaker activity at this subtype).
Researchers use Melanotan II as a reference tool for broad melanocortin receptor pharmacology and as a comparator in studies of selective MC4R agonists such as bremelanotide, which was developed as a Melanotan-II-derived analog with improved MC4R selectivity.
Molecular Architecture
Why a Cyclic Design Enhances Both Potency and Stability
The transition from linear α-MSH to cyclic Melanotan II illustrates a recurring principle in peptide medicinal chemistry: that strategic cyclisation can simultaneously improve metabolic stability (by removing exposed proteolytic cleavage sites) and enhance receptor binding affinity (by pre-organising the peptide into the bioactive conformation).
The lactam bridge in Melanotan II connects the side chains of an Asp residue (position 5 in the original α-MSH numbering, position 1 in the Melanotan II cyclic motif) and a Lys residue (position 10 in α-MSH, position 6 in the cyclic motif). This 23-atom macrocycle constrains the central His-D-Phe-Arg-Trp recognition motif into the receptor-binding conformation, eliminating the entropic cost normally associated with binding linear peptides and enhancing the affinity for melanocortin receptors.
The substitutions within the cyclic peptide further contribute to potency and stability. The N-terminal Nle (norleucine) replaces the native Met-4, eliminating the oxidation-susceptible methionine. The D-Phe at position 7 (D-Phe-7 in α-MSH numbering) is a well-known potency-enhancing substitution originally identified by Hadley and colleagues in linear α-MSH analog studies, the D-stereochemistry produces a constrained backbone conformation that fits the melanocortin receptor binding pocket with enhanced affinity. The C-terminal amide blocks carboxypeptidase cleavage of the C-terminus.
Functionally, Melanotan II binds and activates the human melanocortin receptors MC1R, MC3R, MC4R, and MC5R with affinity comparable to (and in some assays exceeding) native α-MSH. Activity at MC2R, the ACTH receptor, is substantially weaker. The melanocortin receptors are class A G protein-coupled receptors that signal primarily through Gαs/cAMP/PKA cascades, with documented effects on melanin synthesis (MC1R in melanocytes), appetite and energy expenditure regulation (MC3R/MC4R in hypothalamic neurons), exocrine function (MC5R in multiple tissues), and erectile signalling pathways (MC4R in central nervous system circuits).
Research Applications
Broad-Spectrum Melanocortin Receptor Pharmacology
Melanotan II's broad activity across the melanocortin receptor family makes it a uniquely versatile research tool for probing the contribution of individual MC receptors to pigmentation, appetite regulation, energy balance, and other physiological processes.
In pigmentation research, Melanotan II is used as a high-potency MC1R agonist to characterise melanocyte signalling, melanin biosynthesis pathway activation, and tyrosinase enzymatic activity. Cell-based studies have documented effects on melanocyte dendrite extension, transfer of melanin to keratinocytes, and the broader cellular biology of skin pigmentation. The compound serves as a reference MC1R activator in studies of skin pigmentation pathway pharmacology.
Appetite and energy balance research uses Melanotan II as a non-selective MC3R/MC4R agonist. Hypothalamic neuronal preparations characterise the compound's effects on appetite-related circuits in the arcuate nucleus (POMC and AgRP neurons) and the paraventricular nucleus. Comparative work with selective MC4R agonists (bremelanotide) and selective MC3R agonists helps dissect the individual contributions of these receptor subtypes to integrated energy balance regulation.
Erectile pathway research has been documented in published literature using Melanotan II as a melanocortin receptor probe in central nervous system circuits. The MC4R-mediated component of erectile signalling has been characterised in detail, leading to the development of bremelanotide as a MC4R-selective derivative. Researchers also use Melanotan II as a tool in MC5R research (exocrine gland function), in stress-pathway research (interaction with hypothalamic-pituitary-adrenal axis signalling), and in emerging anti-inflammatory research areas where melanocortin receptor activation has documented effects on immune cell function.
Research Overview
Understanding Melanotan II
Melanotan II is a synthetic cyclic peptide analog of α-melanocyte-stimulating hormone (α-MSH), developed by Mac Hadley, Robert Dorr, and colleagues at the University of Arizona in the 1980s as part of a systematic structure-activity programme aimed at producing α-MSH analogs with enhanced metabolic stability and improved receptor binding affinity. The compound has since become one of the most cited synthetic α-MSH analogs in melanocortin research and a benchmark tool for probing the broader melanocortin receptor family.
The structural design, Ac-Nle-cyclo(Asp-His-D-Phe-Arg-Trp-Lys)-NH2, illustrates a recurring principle in peptide medicinal chemistry. Native α-MSH is a 13-residue linear tridecapeptide rapidly degraded by serum proteases. The cyclisation of Melanotan II addresses this limitation through a 23-atom lactam bridge connecting the side chains of an Asp residue and a Lys residue, constraining the central His-D-Phe-Arg-Trp recognition motif into the receptor-binding conformation. This pre-organisation simultaneously improves metabolic stability and enhances receptor binding affinity by eliminating the entropic cost normally associated with binding linear peptides.
Additional substitutions contribute further to potency and stability. The N-terminal Nle (norleucine) replaces the native Met-4, eliminating the oxidation-susceptible methionine. The D-Phe at position 7 (D-Phe-7 in α-MSH numbering) is a well-known potency-enhancing substitution that produces a constrained backbone conformation matching the melanocortin receptor binding pocket. The C-terminal amide blocks carboxypeptidase cleavage. Together these features produce a compact cyclic peptide that retains potent activity across the melanocortin receptor family with substantially improved metabolic stability relative to native α-MSH.
Receptor pharmacology has been characterised in detail. Melanotan II binds and activates the human melanocortin receptors MC1R, MC3R, MC4R, and MC5R with affinity comparable to (and in some assays exceeding) native α-MSH. Activity at MC2R, the ACTH receptor, is substantially weaker. The melanocortin receptors are class A G protein-coupled receptors that signal primarily through Gαs/cAMP/PKA cascades. Each receptor subtype has distinct tissue distribution and biological function: MC1R is expressed primarily in melanocytes and immune cells (with documented roles in pigmentation and anti-inflammatory signalling); MC3R and MC4R are expressed in hypothalamic neurons (with central roles in appetite and energy balance regulation); MC4R is also expressed in central nervous system circuits involved in erectile signalling; MC5R is expressed in multiple tissues including exocrine glands.
In pigmentation research, Melanotan II's MC1R activity drives melanin biosynthesis through tyrosinase activation and downstream melanogenic pathway gene expression. Cell-based studies have documented effects on melanocyte dendrite extension, transfer of melanin to keratinocytes, and the broader cellular biology of skin pigmentation. The compound serves as a reference MC1R activator in studies of skin pigmentation pathway pharmacology and is widely compared to selective MC1R agonists developed for specific research applications.
Appetite and energy balance research uses Melanotan II as a non-selective MC3R/MC4R agonist in hypothalamic neuronal preparations. Effects on appetite-related circuits in the arcuate nucleus (where POMC and AgRP neurons co-express the receptors) and the paraventricular nucleus have been characterised in detail. Comparative work with selective MC4R agonists (including bremelanotide, which was developed as a Melanotan-II-derived analog with improved MC4R selectivity) and selective MC3R agonists helps dissect the individual contributions of these receptor subtypes to integrated energy balance regulation.
Erectile pathway research has been documented in published literature using Melanotan II as a melanocortin receptor probe in central nervous system circuits. The MC4R-mediated component of erectile signalling has been characterised in detail, and the development of bremelanotide as a MC4R-selective derivative reflects the translational research that emerged from this earlier melanocortin pharmacology. Researchers also use Melanotan II as a tool in MC5R research (exocrine function), in stress-pathway research (interaction with hypothalamic-pituitary-adrenal axis signalling), and in emerging anti-inflammatory research areas where melanocortin receptor activation has documented effects on immune cell function and inflammatory pathway markers.
Selected Literature
Peer-reviewed publications cited in this overview
- [1] Hadley ME, Dorr RT. Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides. 2006;27(4):921-930.
- [2] Dorr RT, et al. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci. 1996;58(20):1777-1784.
- [3] Kim CD, et al. The role of melanocortin receptors in skin pigmentation. Pigment Cell Melanoma Res. 2011;24(1):17-29.
- [4] Wessells H, et al. Effect of an α-melanocyte-stimulating hormone analog on penile erection. Int J Impot Res. 2000;12(Suppl 4):S74-S79.
- [5] Cone RD. Studies on the physiological functions of the melanocortin system. Endocr Rev. 2006;27(7):736-749.
Jake F. –
Good MT-II. Arrived fast, reconstituted clean. Anglo is one of the only reliable sources in Canada for this. Same-day shipping is a real plus and glad I found them.
Jordan F. –
Good MT-II from a source I trust now. Came fast, reconstituted clean. Anglo has been consistent across everything I have ordered from them.
Zhang Wei –
Fast shipping, quality product. Powder dissolved easily with no particles at all. Packaging was professional and the vial sealed properly. Will order again.
Connor S. –
Happy with this. Got it in two days, vial looked great. No issues reconstituting. Anglo seems like a solid company and I\’ll be back for my next order.
Max P. –
MTII from Anglo is consistently clean, dissolves with zero cloudiness and the Janoshik COA is thorough. Canadian-made means no customs complications. Fourth order now.
Chloe R. –
The 10mg is excellent value. Documentation is solid and shipping was same-day Xpresspost. Arrived sealed and cold-packed. Really happy with Anglo as my Canadian source.