Bremelanotide

Bremelanotide (formerly PT-141) is a compound under drug development by Palatin Technologies as a treatment for female sexual dysfunction, hemorrhagic shock and reperfusion injury. It functions by activating the melanocortin receptors MC1R and MC4R, to modulate inflammation and limiting ischemia. It was originally tested for intranasal administration in treating female sexual dysfunction but this application was temporarily discontinued in 2008 after concerns were raised over adverse side effects of increased blood pressure. As of March, 2012, Palatin is conducting a human Phase 2B study using a new subcutaneous drug delivery system that appears to have little effect on blood pressure.

Development
Bremelanotide was developed from the peptide Melanotan II which underwent testing as a sunless tanning agent. In initial testing, Melanotan II did induce tanning but additionally caused sexual arousal and spontaneous erections as unexpected side effects in nine out of the ten original male volunteer test subjects.

In studies, bremelanotide was shown to induce lordosis in an animal model and was also effective in treating sexual dysfunction in both men (erectile dysfunction or impotence) and women (sexual arousal disorder). Unlike Viagra and other related medications, it does not act upon the vascular system, but directly increases sexual desire via the nervous system.

A Phase III clinical trial was scheduled to begin in the first half of 2007, but was delayed until August 2007. On August 30, Palatin announced that the U.S. Food and Drug Administration had expressed serious concerns regarding the risk/benefit ratio of bremelanotide with regards to the side effect of increased blood pressure. The FDA stated that it would consider alternate uses for bremelanotide, including as a treatment for individuals who do not respond to more established ED treatments. However, On May 13, 2008, Palatin Technologies announced it had "discontinued development of Bremelanotide for the treatment of male and female sexual dysfunction" while concurrently announcing plans to develop it as a treatment for hemorrhagic shock instead. The company additionally announced intentions to focus its attention on another compound, PL-6983, that causes lower blood pressure in animal models. Palatin has since re-initiated Bremelanotide studies for ED and FSD using a subcutaneous delivery method. On August 12, 2009, the company announced that in a double-blind study of 54 volunteers bremelanotide failed to evoke the hypertensive side effects seen with the nasal delivery system used in prior studies, concluding that "variability of uptake" inherent in intranasal administration of the drug resulted in "increases in blood pressure and gastrointestinal events...primarily related to high plasma levels in [only] a subset of patients" and that subcutaneous administration of the drug circumvented the potential for this side effect. It is now conducting a human Phase 2B study utilizing subcutaneous administration.

Structure
Bremelanotide is a cyclic hepta-peptide lactam analog of alpha-melanocyte-stimulating hormone (alpha-MSH) that activates the melanocortin receptors MC3-R and MC4-R in the central nervous system. It has the amino acid sequence Ac-Nle-cyclo[Asp-His- D -Phe-Arg-Trp-Lys]-OH or cyclo-[Nle4, Asp5, D -Phe7, Lys10]alpha-MSH-(4-10). It is a metabolite of Melanotan II that lacks the C-terminal amide function.