Exploring the Promising Orexin Receptor Pathway

NeurologyLiveOctober 2019
Volume 2
Issue 6

Krithika Subramanian, PhD discusses the orexin receptor pathway, signals within orexin receptors, and much more surrounding the clinical application of orexin receptor antagonists.

The Orexin/Orexin Receptor (OXR) system plays a vital role in multiple functions of the central nervous system (CNS), including modulation of the sleep—wake rhythm, reward systems feeding behavior, energy homeostasis, and cardiovascular responses, as well as cognition and mood.1,2 Orexin-containing neurons are distributed only in the lateral hypothalamus and adjacent areas; however, nerve fibers of orexin neurons project widely into other regions of the brain, and OXRs exhibit a diffuse distribution pattern, partially explaining the diverse and multifaceted functional significance of this neuropeptide/receptor system.1,3 Dysfunction of the orexin system has been implicated in many pathological conditions, including narcolepsy, insomnia, depres- sion, ischemic stroke, addiction, and Alzheimer disease (AD).1 Consequently, drugs targeting the orexin/OXR signaling nexus have gained interest as potential therapeutic agents in treatment of obesity, addiction, and, most significantly, sleep disorders.4-7

Orexins and Orexin Receptors

The 2 orexins, orexin-A and orexin-B (OA and OB; also known as hypocretin-1 and -2), are closely related hypothalamic excit-atory neuropeptides that are generated through proteolysis of a common precursor peptide, prepro-orexin. The orexin gene structure and amino acid sequence are highly conserved across vertebrates, whereas invertebrates seem to lack orexin-like peptides.8 Human orexin mRNA encodes the 131-amino acid prepro-orexin protein, which consists of a 33-amino acid signal peptide followed by the 33 and 28 amino acids corresponding to OA and OB, respectively.1 Both OA and OB are amidated at the C-terminus, whereas OA alone is also cyclized at the N-terminus with a pyroglutamyl residue and has 2 intrachain disul-fide bonds.2,8 The human, mouse, rat, and cow OA amino acid sequences are identical, indicating the significance and conser- vation of OA function in important physiological/neurolog-ical processes.1,8 OB peptide sequences are also highly conserved across species, with the human and rodent OB primary structures differing at only 2 positions.1,8 OA preferentially binds OX1R, with 10- to 100-fold greater affinity than OB, whereas the affinity of OA and OB for OX2R is comparable, indicative of the role of OX2R as a less selective receptor.1,2,8,9

The orexin neuropeptides largely co-localize in the same neurons in the brain, with OA being more lipophilic and stable than OB; OA is also detectable in cerebrospinal fluid (CSF).10 OA crosses the blood—brain barrier to rapidly enter the brain by simple diffusion, whereas it effluxes from the brain to the systemic blood circulation at a rate similar to that of albumin. In contrast, OB undergoes rapid serum degradation prior to CNS entry.11 The 2 OXRs are distributed differently, although orex-in-containing neurons project widely to various brain regions.3 Both receptors are co-expressed in at least some areas of the CNS, such as the ventral tegmental area (VTA), pedunculopon-tine tegmental nucleus, and laterodorsal tegmental nucleus; however, OX1R is preferentially expressed in the locus coeru-leus, whereas OX2R is mainly distributed in the tuberomammil-lary nucleus.1,2 The selective binding of orexins to the OXRs and the distinct distributions of the OXRs are thought to underlie the differential physiological effects of the orexin/OXR pathway.1,2,8 Although most studies on the orexin/OXR pathway have focused on its function in the brain, the pathway may play a role in other peripheral tissues, including testes and adrenal cortex, where small amounts of orexin/OXR expression have been noted.8

Orexin Receptor Signaling

The orexin neuropeptides are packaged into dense core vesicles and synaptically released. Orexin activity shows a mostly phasic pattern and precedes sleep-to-wake transitions by 10 to 20 seconds, consis-tent with the role of orexin neurons in wakefulness and energy homeostasis.10,12 The binding of orexins to the OXRs results in acti-vation of signaling cascades, mediated by activation of at least 3 subtypes of G protein, Gq/11, Gi/o, and Gs, and other proteins such as β-arrestin.1,13,14 The activated effector proteins subsequently modu-late phospholipases, ion channels, and protein kinases, ultimately triggering the activation of various downstream signaling pathways. Gene expression studies have identified the activation of down-stream transcriptional programs triggered by orexin signaling, impli- cating the canonical transforming growth factor β/Smad/bone morphogenic protein, nuclear factor κB, and hypoxic signaling path- ways as some of the most prominent orexin-triggered transcriptional pathways.7 In addition, orexin signaling activates phospholipase C, phospholipase A, phospholipase D, or adenylyl cyclases, resulting in an increase in cytosolic calcium (FIGURE).1 Although their neuro- peptide ligands exhibit similar responses to activation of OX1R and OX2R, the 2 receptors exhibit differential coupling to certain cascades, as indicated by weaker or stronger response activation driven by the 2 receptor systems. In addition, persistent orexin stim-ulation has been shown to induce programmed cell death in recom- binant cellular models as well as in cancer cells, especially in colon cancer cells1,7,13,15,16; orexin signaling—mediated induction of mito- chondrial apoptosis via recruitment of the SHP2 phosphotyrosine phosphatase is the mechanism underlying the potential anticancer effects of this pathway.15,16

Three main ionic mechanisms are involved in mediating the acute effects of orexins: inhibition of potassium channels, which increases excitability in some neurons8,17; induction of a rapid and sustained rise in intracellular calcium through voltage-gated calcium chan- nels, through transient receptor potential channels, or from intracel- lular stores1,8,18-21; and activation of the sodium/calcium exchanger, which can also stimulate excitability of target neurons.8,22,23 In addi-tion, orexins can act presynaptically on nerve terminals to induce γ-aminobutyric acid (GABA) or glutamate release, which can engender other effects on downstream neurons.8,14 Orexin signaling can also induce long-lasting increases in neuronal excitability. For instance, in the VTA, orexins increase the number of cell membrane—localized N-methyl-D-aspartate receptors, enabling increased and prolonged glutamate-mediated responsiveness in neurons; further-more, orexin/OX1R signaling in the VTA has been shown to have a critical role in behavioral sensitization to cocaine.1,8,24 Altogether, the above mechanisms explain the general neuronal excitatory effects of orexins in regulation of arousal, including orexin-mediated GABA-driven appetite modulation. The effects of the orexin/OXR pathway in the CNS and the potential impacts of stimulation/antagonism of this pathway are summarized in TABLE 1.16

Targeting the Orexin Pathway in Neurological Disorders

An accumulating body of evidence implicates dysfunction of the orexin/OXR system in several neurological disorders, including narcolepsy, insomnia, depression, addiction or ethanol/cocaine/ nicotine-seeking behavior, and AD.1,2,8 The broad function of this pathway and its involvement in the pathogenesis of neurolog-ical conditions provides opportunities for clinical targeting of the orexin/OXR pathway using agonists, antagonists, or potentiators.7 For instance, most patients with narcolepsy have low or undetect- able levels of orexin, although the absence is not driven by muta- tions in genes encoding orexins or OXRs.25-28 Moreover, knockout of the orexin gene in rodents results in a phenotype that resembles human narcolepsy with cataplexy.1,29

Whereas deficiencies in orexin signaling/function are involved in narcolepsy, overexpression or hyperactivation of this signaling pathway correlates with the pathogenesis of insomnia. Insomnia is a chronic and pervasive sleep disorder characterized by difficulty initiating sleep and/or staying asleep, which eventually leads to impairments in daytime functioning.30 Orexin neuropeptide levels have a significant correlation with the time of day, with higher OA levels in CSF coinciding with wakefulness or diurnal periods.1 In contrast, overexpression of the orexin/OXR system disrupts the sleep/wake cycle; for instance, in 1 study,31 plasma OA levels were significantly higher in subjects with insomnia disorder compared with normal sleepers, and the increase in OA levels correlated with the course and severity of insomnia. Given the critical role of the orexin/OXR pathway in modulation of the sleep/wake cycle and wakefulness, 2 classes of OXR antagonists, single OXR antago-nists (SORAs) and dual OXR antagonists (DORAs), are being devel- oped and tested as potential agents for the treatment of insomnia in various animal models and clinical studies.1,5

Clinical Application of Orexin Receptor Antagonists

To date, the most extensive research into targeting of the OXR system for clinical treatment has been carried out in insomnia. Utilization of orexin/OXR modulators in insomnia is particularly interesting, as it provides an additional and alternative pharmacological avenue for exploration compared with the more common GABA agonist—mediated or other treatments, which the US FDA pinpointed as having restricted efficacy profiles.6 Clinically relevant OXR-targeted agents include SORAs and DORAs; SORAs exhibit recep-tor-type selectivity, as they display binding affinity for either OX1R or OX2R, whereas DORAs act in a nonspecific manner at both OX1R and OX2R.6 Targeting of both OXRs has gained more traction in clinical settings, based on data suggesting that both OXRs are involved in transitioning between sleep stages. Whereas clinical studies are being conducted to evaluate some SORAs, including seltorexant (MIN-202; OX2R-selective), most SORAs have been used to probe orexin pathway functions.32-37

DORAs, including almorexant (ACT-078573), suvorexant (Belsomra), filorexant (MK-6096), SB-649868, and lemborexant (E-2006) have been examined in clinical trials, with suvorexant gaining FDA approval in 2014 as a Schedule IV controlled substance for treatment of insomnia (TABLE 26).32,33,38-42

Although almorexant showed initial positive effects in the treat- ment of insomnia symptoms, clinical advancement was discon- tinued in 2011 due to safety concerns related to abnormal elevated liver enzyme concentrations.6 Suvorexant is a highly potent DORA that inhibits OA and OB binding to OX1R and OX2R, respectively, suppressing wakefulness.32 Several randomized, double-blind, place- bo-controlled trials have evaluated the efficacy, safety, and tolera-bility of suvorexant in the treatment of insomnia. In 2 phase 3 trials, 1 lasting 3 months and the other lasting 1 year, suvorexant proved effective at improving sleep onset and maintenance in adults with insomnia.6,32 Existing data indicate that suvorexant is well tolerated by elderly (aged ≥65 years) and nonelderly (aged 18-64 years) men and women with insomnia at doses up to 20 mg, with somnolence being the most frequent adverse event (AE) reported.43-46 Although suvorexant doses of 10 to 80 mg have been evaluated in humans, FDA-approved doses are 5 mg, 10 mg, 15 mg, and 20 mg due to concerns about AEs experienced by patients at higher doses (30 mg and 40 mg).6,32 Filorexant appears to have a favorable pharmaco-kinetic profile, and its short half-life (3 to 6 hours) relative to other DORAs allows for a favorable residual effect profile.6,47 A double-blind, placebo-controlled, randomized study of filorexant showed significantly improved sleep efficiency in nonelderly patients with insomnia; dose-related improvements were observed in both sleep onset and maintenance outcomes.48 As with suvorexant, somnolence was the most prominent residual effect, but it was significant only at doses above 10 mg.6 Notably, Merck has discontinued or placed on hold its development of filorexant. SB-649868 is an orally adminis- tered DORA that has exhibited improved sleep induction, improved sleep maintenance, and reduced sleep latency in clinical studies of male patients with insomnia.49 This DORA has been generally well tolerated at doses up to 60 mg, and minimal AEs, such as somno- lence and fatigue, have been reported.6,49 Lemborexant, another DORA, demonstrated efficacy in significantly improving mean sleep efficiency compared with placebo, including shortening sleep latency and wake after sleep onset in patients with insomnia, while minimizing next-morning sleepiness, in a phase 2 clinical trial.6,50 Clinical trials of lemborexant have been completed in patients with general insomnia (NCT02952820; phase 3) and are currently ongoing in patients with irregular sleep/wake rhythm disorder and AD dementia (NCT03001557; phase 2). The most significant AEs reported with lemborexant include somnolence, headache, and sleep paralysis.6


The orexin/OXR system is involved in the regulation of multiple CNS functions, and perturbation of this neuropeptide signaling system causes imbalances in orexin-containing and associated neurons, thereby impairing neurotransmitter systems and potentiating the pathogenesis of various neurological disorders. Selective targeting of the orexin/OXR system, using agonists or antagonists that target either or both OXRs, has emerged as a potential pharmaceutical intervention to treat some neurological condi- tions, especially insomnia. Further understanding of the molecular underpinnings of the orexin/OXR pathway in the CNS as well as in peripheral tissues, along with pharmacological and clinical studies of SORAs and DORAs in insomnia/narcolepsy and other neurolog- ical conditions, are warranted to actualize the clinical potential of orexin/OXR pathway—directed agents


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