Bremelanotide
Encyclopedia
Bremelanotide is a compound under drug development
by Palatin Technologies as a treatment for hemorrhagic shock and reperfusion injury
. It functions by activating the melanocortin
receptors MC1R and MC4R, to modulate inflammation and limiting ischemia
.
It was originally developed for use in treating sexual dysfunction
but this application was temporarily discontinued in 2008, after concerns were raised over adverse side effects of increased blood pressure
. Currently, Palatin is in negotiations with the FDA to resume Human Phase 2 studies using a new subcutaneous drug delivery system that appears to have little effect on blood pressure
.
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 effect
s 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 they 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 model
s. 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 in discussions with the FDA to resume Human Phase 2 studies utilizing subcutaneous administration.
lactam
analog
of alpha-melanocyte-stimulating hormone
(alpha-MSH) that activates the melanocortin receptor
s 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
.
Drug development
Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
by Palatin Technologies as a treatment for hemorrhagic shock and reperfusion injury
Reperfusion injury
Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. The absence of oxygen and nutrients from blood during the ischemic period creates a condition in which the restoration of circulation results in inflammation and...
. It functions by activating the melanocortin
Melanocortin
The melanocortins are a group of peptide hormones which include adrenocorticotropic hormone and the different forms of melanocyte-stimulating hormone . They can be synthetic . In humans they can be endogenously produced from proopiomelanocortin in the pituitary gland...
receptors MC1R and MC4R, to modulate inflammation and limiting ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
.
It was originally developed for use in treating sexual dysfunction
Sexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
but this application was temporarily discontinued in 2008, after concerns were raised over adverse side effects of increased blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
. Currently, Palatin is in negotiations with the FDA to resume Human Phase 2 studies using a new subcutaneous drug delivery system that appears to have little effect on blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
.
Development
Bremelanotide was developed from the peptidePeptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
Melanotan II
Melanotan II
Melanotan II developed at the University of Arizona is a synthetic analog of the naturally occurring melanocortin peptide hormone alpha-melanocyte stimulating hormone that in usage has been shown to have melanogenesis and aphrodisiac effects in preliminary studies and clinical trials...
which underwent testing as a sunless tanning
Sunless tanning
Sunless tanning Sunless tanning Sunless tanning (also known as UV-free tanning, self tanning, spray tanning (when applied topical, or fake tanning) refers to the application of chemicals to the skin to produce an effect similar in appearance to a suntan...
agent. In initial testing, Melanotan II did induce tanning but additionally caused sexual arousal
Sexual arousal
Sexual arousal, or sexual excitement, is the arousal of sexual desire, during or in anticipation of sexual activity. Things that precipitate human sexual arousal are called erotic stimuli, or colloquially known as turn-ons. There are many potential stimuli, both physical or mental, which can cause...
and spontaneous erections as unexpected side effect
Therapeutic effect
A therapeutic effect is a consequence of a medical treatment of any kind, the results of which are judged to be desirable and beneficial. This is true whether the result was expected, unexpected, or even an unintended consequence of the treatment...
s in nine out of the ten original male volunteer test subjects.
In studies, bremelanotide was shown to induce lordosis
Lordosis behavior
Lordosis behavior, or mammalian lordosis, is a sexual response in mammals, such as mice and cats, that consists of a ventral arching of the spine. During lordosis, the spine curves so that the apex points in the ventral direction. That is, the spine arches inward toward the abdomen.Lordosis aids in...
in an animal model and was also effective in treating sexual dysfunction
Sexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
in both men (erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
or impotence) and women (sexual arousal disorder
Sexual arousal disorder
Sexual arousal disorder is characterized by a lack or absence of sexual fantasies and desire for sexual activity in a situation that would normally produce sexual arousal, or the inability to attain or maintain typical responses to sexual arousal. The disorder is found in the DSM-IV...
). Unlike Viagra
Sildenafil
Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension . It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer...
and other related medications, it does not act upon the vascular system
Circulatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...
, but directly increases sexual desire
Libido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
via the nervous system.
A Phase III clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
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
Risk-benefit analysis
Risk–benefit analysis is the comparison of the risk of a situation to its related benefits. Exposure to personal risk is recognized as a normal aspect of everyday life. We accept a certain level of risk in our lives as necessary to achieve certain benefits. In most of these risks we feel as though...
ratio of bremelanotide with regards to the side effect of increased blood pressure. The FDA stated that they 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 model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
s. 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 in discussions with the FDA to resume Human Phase 2 studies utilizing subcutaneous administration.
Structure
Bremelanotide is a cyclic hepta-peptidePeptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
lactam
Lactam
A lactam is a cyclic amide. Prefixes indicate how many carbon atoms are present in the ring: β-lactam , γ-lactam , δ-lactam...
analog
Analog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
of alpha-melanocyte-stimulating hormone
Alpha-Melanocyte-stimulating hormone
alpha-Melanocyte-stimulating hormone , also known as alpha-melanotropin, alpha-melanocortin, or alpha-intermedin, is a naturally-occurring endogenous peptide hormone of the melanocortin family, with a tridecapeptide structure and the amino acid sequence...
(alpha-MSH) that activates the melanocortin receptor
Melanocortin receptor
Melanocortin receptors are members of the rhodopsin family of 7-transmembrane, G protein-coupled receptors.There are five known members of the melanocortin receptor system each with differing specificities for melanocortins:...
s MC3-R
Melanocortin 3 receptor
Melanocortin receptor 3 is a protein that in humans is encoded by the MC3R gene.-Further reading:...
and MC4-R
Melanocortin 4 receptor
Melanocortin receptor 4 is a protein that in humans is encoded by the MC4R gene. It encodes the MC4 protein, a G-protein coupled receptor that binds α-melanocyte stimulating hormone...
in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. 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
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
of Melanotan II that lacks the C-terminal amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
function
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
.
External links
- Palatin Technologies The company that has developed bremelanotide. bremelanotide (PT-141) patent (Appl. No.:040547)
- US 6,579,968 bremelanotide (PT-141) patent (Appl. No.:066501)
- Bremelanotide Edguider Forum