Melanocortins have important roles in a variety of bodily functions, for example, from controlling skin pigmentation to sexual response. Melanocortins act by binding to and activating melanocortin receptors and five different melanocortin receptors have been identified.
Melanocortin Receptor Agonists mimic the effects of melanocortins and activate several or specific melanocortin receptors to produce their effects.
How do Melanocortin Receptor Agonists Work?
Melanocortins are a group of peptide (short-chain amino acids) hormones that are derived from proopiomelanocortin (POMC), a protein that is made in the pituitary gland.
Melanocortins have important roles in regulating a variety of bodily functions such as inflammation, infection, obesity, skin pigmentation, and steroidogenesis (the process by which cholesterol is converted into biologically active steroid hormones). Known melanocortins include adrenocorticotropin hormone (ACTH), α-melanocyte stimulating hormone (α-MSH), beta-melanocyte-stimulating hormone (β-MSH), and gamma-melanocyte-stimulating hormone (γ-MSH).
Melanocortins act by binding to and activating melanocortin receptors. Five melanocortin receptors have been identified:
- Melanocyte-stimulating hormone receptor (MSH-R), now termed MC1-R: Expressed on melanocytes and responsible for different pigmentations
- Adrenocorticotropin receptor (ACTH-R)
- MC3-R
- MC4-R: Present throughout the central nervous system. Implicated in the control of food intake, energy expenditure, and modulates erectile function and sexual behavior
- MC5-R.
Bremelanotide is a nonselective melanocortin receptor agonist that activates several melanocortin receptors, most notably MC4R and MC1-R. The mechanism for the improvement of hypoactive sexual desire disorder is unknown, but it has been shown to be effective for the treatment of hypoactive sexual desire disorder in women and erectile dysfunction in men.
Afamelanotide is a melanocortin receptor agonist that binds predominantly to MC1-R. This increases the production of eumelanin in the skin independently of exposure to sunlight or artificial UV light sources and is used to allow adult patients with a history of phototoxic reactions from erythropoietic protoporphyria to be exposed to light without experiencing pain.
Setmelanotide is a selective MC4-R agonist with 20-fold less activity at MC3-R and MC1-R. MC4-R is involved in the regulation of hunger, satiety, and energy expenditure. In people with certain deficiencies, setmelanotide may re-establish MC4-R activity to reduce hunger and promote weight loss.
What are Melanocortin Receptor Agonists Used For?
Currently available melanocortin receptor agonists are used to treat:
- Erythropoietic protoporphyria. This is a rare, inherited, disorder caused by a deficiency of the enzyme ferrochelatase. A major symptom is severe pain from exposure to sunlight and some types of artificial light, such as fluorescent lights. (Afamelanotide)
- Low sexual desire in women who have not gone through menopause and have not had a low sexual desire in the past. (Bremelanotide)
- Long-term weight management in adults and children aged 6 years and older with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency who meet certain criteria. (Setmelanotide).
What are the Side Effects of Melanocortin Receptor Agonists?
Side effects of melanocortin receptor agonists may include:
- A slow heartbeat
- Darkening of the gums or skin (especially on the face or breasts), which may be permanent, even after discontinuing the agent. People with darker skin color may be more at risk
- High blood pressure (causing symptoms of a severe headache, blurred vision, and pounding in your neck or ears)
- Hot flashes or flushing
- Nausea, which may be severe
- Vomiting
- Respiratory tract infections
- Tiredness or fatigue.
