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Section V. MISCELLANEOUS DRUGS
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Bremelanotide (Vyleesi): A Melanocortin
Receptor Agonist for Treating Female
Hypoactive Sexual Desire Disorder
Yan Wang
16
1. Background
Hypoactive sexual desire disorder (HSDD)
of interest in sex to the point of personal or relationship distress. It affects both men and
women but is most common in women. This sexual dysfunction affects about 10% of
adult women. Women with HSDD lack or loss of motivation to participate in sexual
activity. Sexual dysfunction
well-being.
Bremelanotide (BMT, VyleesiTM, 1) was approved by FDA to treat acquired,
generalized HSDD in June 2019.3 Vyleesi is administered by patients as a 1.75 mg
subcutaneous injection in the abdomen or thigh using a single-use auto-injection pen,
Chemistry and Pharmacology of Drug Discovery, First Edition. Edited by Jie Jack Li.
© 2025 John Wiley & Sons, Inc. Published 2025 by John Wiley & Sons, Inc.
1, 2
refers to a person’s chronic or ongoing lack
adversely impacts the quality of life in women and general
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Chemistry and Pharmacology of Drug Discovery
45 minutes before anticipated sexual activity. Before BMT approval, Flibanserin
(AddyiTM, 2)4 was the only FDA-approved medication for female HSDD. Bupropion (3)
and buspirone (4) may be considered off-label treatments for female HSDD despite
limited safety and efficacy data.
Sexual desire is believed to be regulated by neuromodulators (neurotransmitters
and hormones) of excitatory pathways [e.g. dopamine (5), norepinephrine (6),
melanocortins (see Section 2.2), oxytocin (7)] and inhibitory pathways (e.g. serotonin (8),
5
opioids, endocannabinoids (9, 10)).
See Figure 1 on excitatory and inhibitory effects of
neurotransmitters and hormones on sexual desire.
Figure 1. Excitatory (+) and inhibitory (–) effects of neurotransmitters and hormones on
sexual desire
Flibanserin’s mechanism of action is exerted through serotonin 1A (5HT-1A)
receptor agonism and serotonin 2A (5HT-2A) receptor antagonism. This process reduces
serotonin inhibition of excitatory neurotransmitters and thus indirectly increases the
release of dopamine (5) and norepinephrine (6).
6, 7
BMT (1) is an agonist of melanocortin
receptors (MCRs), and it nonselectively activates several of the receptor subtypes, of
which subtype 4 is at relevant therapeutic doses.8Melanocortin-4 receptor (MC4R) is
predominantly
expressed in the brain’s medial preoptic area (mPOA) of the
hypothalamus and is important for female sexual function.
Addyi (2) is an oral tablet taken once daily. It must be taken at bedtime to
reduce the risk of low blood pressure, etc. There is concern about consuming
alcoholic
drinks before taking Addyi (2) at bedtime. Vyleesi (1) is a subcutaneously administered,
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Chapter 16. Bremelanoide (Vyleesi)
on-demand therapy. It is used as needed, at least 45 minutes before anticipated sexual
activity. It can be safely co-administered with ethanol.
9, 10
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Chemistry and Pharmacology of Drug Discovery
2. Pharmacology
2.1. MCRs Location and Functions
The MCR system consists of five 7-transmembrane G-protein-coupled receptors
(GPCRs), generally called MC1R, MC2R, MC3R, MC4R, and MC5R. They signaled
mainly through intracellular cyclic adenosine monophosphate.
MC1R is found primarily in the periphery, especially in the skin; the MC2R in
the adrenal gland; the MC3R in the brain and periphery; the MC4R in the brain and
periphery; and the MC5R throughout the body.
The MCRs are involved in a diverse number of physiological functions. MC1R
governs the mammalian skin and hair color by regulating melanin production. It plays an
important role in the pigmentation process. MC2R, also known as the ACTH receptor, is
located in the adrenal cortex and controls glucocorticoids (stress hormones). MC3R is
responsible for body weight and appetite control. Recent studies also revealed that MC3R
has crucial functions such as regulating hunger, appetite, and body weight. MC5R plays a
key role in governing immune reactions and inflammatory responses.
MC4R is predominantly expressed in the mPOA of the hypothalamus in the
brain. It is a critical regulator of energy homeostasis, including food intake and
expenditure.
BMT (1) may affect female sexual desire by activating presynaptic MC4Rs on neurons in
the mPOA of the hypothalamus, leading to increased release of dopamine (5). This
excitatory neurotransmitter increases sexual desire (see Figure 1).
It is also important for female sexual function. Animal studies suggest that
11–13
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Chapter 16. Bremelanoide (Vyleesi)
2.2. Melanocortin Peptides
The natural agonist ligands (Table 1) for MCRs are derived by processing a primordial
animal gene product, proopiomelanocortin (POMC). The ligand for the MC2R is
adrenocorticotropic hormone (ACTH, 11), a larger processed peptide from POMC. The
natural
stimulating hormone (α-MSH, 12) and related peptides from POMC (β-MSH 13 and γ
MSH, 14, and
conserved throughout evolution.
Table 1. Sequences of human melanocortins
ACTH (11) Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp- Gly-Lys-Pro-Val-Gly-Lys-Lys-
α-MSH (12) Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH
β-MSH (13) Asp-Glu-Gly-Pro-Tyr-Arg-Met-Glu-His-Phe-Arg-Trp-Gly-Ser-Pro-Pro-
γ
γ
(Table
MC3R and MC4R. See Table
Table 2. Pharmacological properties of MCR subtypes
ligands for the other four MCRs are smaller peptides, including α-melanocyte
3
γ
-MSH, 15). They all contain the sequence His-Phe-Arg-Trp that is
Peptide
14
Sequences
name
Arg-Arg-Pro-Val-Lys-Val-Tyr-Pro-Asn-Gly-Ala-Glu-Asp-Glu-Ser-AlaGlu-Ala-Phe- Pro-Leu-Glu-Phe
Lys-Asp
1
-MSH (14) Lys-Tyr-Val-Met-Gly-His-Phe-Arg-Trp-Asp-Arg-Phe-NH
3
-MSH (15) Lys-Tyr-Val-Met-Gly-His-Phe-Arg-Trp-Asp-Arg-Phe-Gly-Arg-Arg-
2
Asn-Ser-Ser-Ser-Ser-Gly-Ser-Ser-Gly-Ala-Gly-Gln
Agouti signaling protein (ASIP) and AgRP are endogenous MCRs antagonists
2). ASIP is selective for MC1R and MC4R, but AgRP is a selective antagonist for
2 on pharmacological properties of MCR subtypes.
MCRs
MC1R α-MSH = ACTH > β-MSH >> γ-MSH/Agouti
MC2R ACTH
MC3R α-MSH = β-MSH = γ-MSH = ACTH/AgRP
MC4R
MC5R
α-MSH = ACTH > β-MSH >> γ-MSH/Agouti, AgRP
α-MSH > ACTH > β-MSH > γ-MSH
Agonist potency/endogenous antagonists
1
2
-
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