Belsomra

Belsomra, also known as Suvorexant, is an orexin receptor antagonist medication used for insomnia ^[1]. While most other insomnia drugs, like Ambien and Lunesta, are Gamma-aminobutyric acid (GABA) receptor agonists and work to slow down neuronal firings, Belsomra is the first drug to target orexin ^[2]. Orexin, also known as hypocretin, is a neurotransmitter that binds to receptors in order to cause alertness and wakefulness. By targeting orexin's receptors, Belsomra cuts off the signals causing one to be awake, and will result in sleep ^[1]. Due to this inhibition, a common side effect of Belsomra is somnolence, or next day drowsiness ^[3].

Function

The orexin neuropeptides, Orexin-A and Orexin-B, can excite neurons in the brain and affect multiple systems, including the acetylcholine, dopamine, histamine, and norepinephrine systems ^[4][5][6]. These orexin neuropeptides bind to two subtypes of receptors, Orexin receptor 1 and Orexin receptor 2, both of which are G protein coupled receptors (GPCRs) ^[7]. The GPCRs can sense a molecule outside the cell and send a signal through transduction in order to cause the cells to respond ^[8]. Thus, binding of the two can control wakefulness in humans. In studies, Orexin-B has shown to be more selective in binding, choosing to bind to Orexin receptor type 2 a majority of the time. Orexin-A has shown an equal selectivity at both types of receptors ^[4]. Belsomra is a dual orexin receptor antagonist, and has the ability to block both Orexin receptors 1 and 2, thus inhibiting the neuropeptides from binding. By blocking this interaction, sleep can occur ^[1].

Structural Highlights

Belsomra assumes a conformation similar to that of a horseshoe when binding to the orthosteric binding pocket of either orexin receptor 1 or orexin receptor 2. Through steric hindrance, this horseshoe conformation halts transmembrane domain movement by making contact with the alpha-helices of all transmembrane domains except for the first one upon entering the binding site of the receptor. ^[9]. Types of interactions between Belsomra and both orexin receptor subtypes include Van Der Waals interactions, aromatic packing via the pi bonds of aromatic amino acids, and hydrogen bonding. The most significant hydrogen bond occurs between the amide of Belsomra and the side chain of Asn318 (Orexin receptor 1), and the side chain of Asn324 (Orexin receptor 2) ^[9]. Water molecules also play a role in hydrogen bonding via formation of bridges between the Belsomra drug itself and the orexin receptors’ Asn324 and His350. ^[9]. Structural differences of the two orexin receptors’ binding sites involve only two amino acids: Thr135 in receptor 2 is Ala127 in receptor 1, while Thr111 in receptor 2 is Ser103 in receptor 1. ^[9][10].

Relationship to Insomnia

Insomnia is a sleep disorder that is seen to be mostly caused by stress, and results in inefficient cooperation between the sleep and wake pathways of the arousal system^[11]. The branch of the arousal system that reaches the lateral hypothalamus, which contains the melatonin-concentrated orexin neuropeptide signaling system, is one of the most significantly affected areas of the wakefulness network. This orexin system is a major promoter for wakefulness and is most active during efforts to sustain and maintain arousal, while showing little activity during sleep. Orexins show little activity during sleep because the systems to promote wakefulness are blocked by neurons of the ventrolateral preoptic nucleus and thus cannot fire. During sleep, these VLPO neurons are activated and form dense clusters containing GABA and galanin, which aid in their function as inhibitors for arousal^[12]. With insomnia, the structures regulating a patient’s arousal system are unusually active during sleep, and thus the system fails to deactivate. Belsomra is a drug that counteracts this by serving as a dual antagonist in its interactions with Orexin receptors 1 and 2, in the aim of deactivating the arousal system in order for patients to sleep with little orexin activity present. This could also exacerbate the symptoms of narcolepsy, as the already little orexin activity would be diminished at great risk to patients with the sleep disorder^[13].

See also:

• Receptor
• Transmembrane (cell surface) receptors
• G protein-coupled receptors