Melanotan II

Melanotan II belongs to a group of peptides called the melanotropin peptides. Other peptides belonging to this group are ACTH (adrenocortropic hormone) and the melanocyte-stimulating hormones (MSH).

Classification, Actions, Mechanisms:

The MSHs contribute to pigmentation and also play a role as a hypothalamic satiety signal [1]. Melanocortins also have been demonstrated to play a role in lipolysis of adipocytes, thermal control, sexual function, and cognition [1, 2]. Further, leptin exerts its action partly by activation of the melanocortin system in the brain [3]. Further, the MCR (melanocortin receptors), to which MTII binds, play a key role in eating behavior in humans [3]; Perboni et al write: MC4R activity affects meal size and meal choice but not meal frequency, with the type of diet affecting the efficacy of MC4R agonists to reduce food intake [3].

Dorr, et al, demonstrated in a pilot trial study using human subjects that significant change in pigmentation (specifically, darkening) occurred after just five applications of MTII (applied every other day via subcutaneous injection) as measured by visual perception as well as by quantitative reflection [5]. They also noted that penile erection consistently occurred concomitantly with "stretching and yawning" between one and five hours after application of MTII in males via subcutaneous injection [5]. Mild nausea was observed at most MTII dosage levels, although no treatment was required and all subjects opted to continue the trials for the duration of the two-week study [5].

Wessells et al concluded that "Melanotan-II is a potent initiator of erections in men with psychogenic erections in men with psychogenic erectile dysfunctions and has manageable side effects at a dose of 0.025mg/kg" based on the findings of their study that: In 8 of 10 men treated with Melanotan-II clinically apparent erections developed. Mean duration of tip rigidity greater than 80% was 38.0 minutes with Melanotan-II and 3.0 with placebo (p=0.0045). Transient side effects of nausea, stretching and yawning, and decreased appetite were reported more frequently after injections of Melanotan-II than placebo but none required treatment" [6].

The unique combination of effects, i.e. penile erection in addition to the hunger/satiety modulation properties, of Melanotan II as demonstrated in clinical trials renders it "complicate[d]" in applied treatment of obesity [3]. The CNS/MCR system plays a role in controlling adiposity through nutrient partitioning as well as cellular lipid metabolism independent of nutrient intake [3]. Pharmacologically inhibiting MCR in rats, and genetically disrupting MCR4 expression in mice, has resulted in lipid uptake, triglyceride synthesis, and fat accumulation in white adipose tissue "directly and potently." Conversely, increased CNS-MCR signalling increases lipid mobilization [3].

On the topic of MTII as a potential obesity treatment agent, Perboni et al write:

MC3R has been suggested to play a role in nutrient partitioning. Although agonists of the MC3R would not be expected to produce dramatic weight loss, they may favor a more beneficial partitioning of nutrients ... development of dual MC4 and MC3 receptor agonists has been addressed in order to reduce weight dramatically, as well as improve the metabolic co-morbidities of obesity significantly [3]. Melanotan II binds to both of these receptors.

Of a study performed on rats, Banno summarizes:

...data showed that food intake and body weight were decreased by chronic administration of MTII and that insulin sensitivity as well as glucose tolerance was improved by MTII in those rats. The serum TG [triglyceride] levels were also decreased by MTII, and these effects persisted for at least 25 days. Thus, our data demonstrated that melanocortin agonists administered peripherally ameliorated obesity, insulin resistance and hypertriglyceridemia in OLETF rats [4].

Banno et al also refer to other data, and synthesize these data with their own to conclude, similarly to Perboni, that "melanocortin agonists [such as MTII] could well be a promising treatment for obesity in humans":

...[in a study on humans,] there was not full compensation in food intake, and body weight remained significantly lower for about a month in the present study. These data suggest that melanocortin agonists could well be a promising treatment for obesity in humans...administration of MSH/ACTH4-10, a MC4R agonist, was shown to decrease body weight and body fat in healthy and normal weight humans without apparent side effects [4].

Conclusion:

Trends in current research suggest that Melanotan II and other MSHs will likely be implemented in various capacities for treatment of obesity, metabolic syndrome, and comorbid disorders. While trials for various delivery systems are underway for MTII and similar peptides to be used for treatment of erectile dysfunction and for aesthetic purposes (harnessing the well-known pigmentation properties of the MSHs), FDA approval for treatment of more serious issues such as the abovementioned is more likely. The MSH are unique in their disparate and broad actions in the body.

references:

[1] Hruby VJ, Lu D, Sharma SD, Castrucci AL, Kesterson RA, al-Obeidi FA, et al. Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-cyclo[Asp5, D-Phe7,Lys10] alpha-melanocyte-stimulating hormone-(4–10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J Med Chem 1995;38(18):3454–61.

[2] Molinoff PB, Shadiack AM, Earle D, Diamond LE, Quon CY. PT- 141: a melanocortin agonist for the treatment of sexual dysfunction. Ann N Y Acad Sci 2003;994:96–102.

[3] PEPTIDES IN ENERGY BALANCE AND OBESITY (Book), Gema Frühbeck (ed.), CAB International 2009, Subsection: Anorexigenic Peptides, Perboni, S., Ueno, G., Mantovani, and Inui, A. pp. 45-47

[4]Banno R. The melanocortin agonist melanotan II increases insulin sensitivity in OLETF rats. Peptides Volume 25, Issue 8, August 2004, pp. 1279-1286

[5]Dorr R.T., Lines R, Levine N., Brooks C., Xiang L., Hruby V.J., Hadley M.E. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci, 1996;58(20), pp.1777-84.

[6] Wessells H., Fuciarelli K., Hansen J., Hadley M.E., Hruby V.J., Dorr R., Levine N. Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study. J Urol. 1998 Aug;160(2): pp. 389-93.

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