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OREXIN RECEPTOR ANTAGONISTS:A NEW CLASS OF SLEEPING PILL

PRESENTED BY

CHAITRA. N.

1ST YEAR M-PHARM.

DEPT.OF PHARMACOLOGY.

PESCP,BANGALORE.

INTRODUCTION TO HYPOTHALAMUS

Hypothalamus is small part of the diencephalon located inferior to thalamus.

It is composed of a dozen of nuclei.

Four major regions of hypothalamus where nuclei are located are :

Mammillary region - located adjacent to the midbrain. It includes mammillarybodies & posterior hypothalamic nuclei serve as relay stations for reflexes related to the sense of smell.

Tubular region includes the dorsomedial nucleus, ventromedial nucleus, arcuate nucleus connects the pituitary gland to the hypothalamus.

Supraoptic region is located superior to the optic chiasm contains the paraventricular nucleus, supraoptic nucleus, anterior hypothalamic nucleus &suprachiasmatic nucleus.

Preoptic region is located anterior to the supraoptic region. It contains the medialand lateral preoptic nuclei.

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Control of the ANS.

Production of hormones.

Regulation of emotional and

behavioral patterns.

Regulation of eating and drinking.

Control of body temperature.

Regulation of circadian rhythms and

states of consciousness.

The suprachiasmatic nucleus of the

hypothalamus serves as the body’s

internal biological clock as it establishes

the patterns of sleep-wake cycle.

FUNCTIONS OF HYPOTHALAMUS

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BRAIN WAVES Brain neurons generate millions of nerve impulses which collectively form

electrical signals called Brain waves.

Brain waves generated by neurons can be detected by sensors called electrodes

placed on the forehead & scalp. A record of such waves is called an

Electroencephalogram (EEG).

Electroencephalogram are useful both in studying normal brain functions such

as changes that occur during sleep and in the diagnosis of various brain disorders like

epilepsy, tumors, trauma, metabolic abnormalities and degenerative diseases.

Four types of brain waves:

Alpha waves.

Beta waves.

Theta waves.

Delta waves.13/2/2015 3

STAGES OF SLEEP

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Sleep: A natural periodic state of rest for the mind & body, in which the eyes usually

close & consciousness is completely or partially lost, so that there is a decrease in

bodily movement & responsiveness to external stimuli.

Sleep disorders are changes in sleeping patterns or habits. It can affect overall

health, safety and quality of life.

Signs and symptoms of sleep disorders include excessive daytime sleepiness,

irregular breathing or increased movement during sleep, difficulty sleeping and

abnormal sleep behaviors.

Causes for the sleep disorders

Pain

Cardiovascular Disease

Psychiatric Diseases

Neurological Diseases

Metabolic Disorders

SLEEP DISORDERS

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INSOMNIA

Sleep disorder in which there is an inability to fall asleep or to stay asleep for long

time.

Symptoms includes prolonged night awakenings,

daytime tiredness or sleepiness, irritability,

depression or anxiety, tension headaches.

PARASOMNIAS

Sleep disorders that involve abnormal movements, behaviors, emotions,

perceptions & dreams that occur while falling asleep, sleeping, between sleep

stages or during arousal from sleep.

Symptoms includes sleep walking and talking,

confusional arousals, night terrors & sleep

related groaning, bed wetting.

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DYSSOMNIAS

It is a primary disorder of initiating or maintaining sleep or of excessive

sleepiness & is characterized by a disturbance in the amount, quality or

timing of sleep.

Symptoms includes abnormal amount of sleep, abnormal quality of sleep,

abnormal timing of sleep, impaired concentration.

NARCOLEPSY

It is a neurological disorder that affects the control of sleep and

wakefulness characterized by extreme tendency to fall asleep whenever

in relaxing surroundings.

Symptoms includes excessive daytime sleepiness, night time

wakefulness, cataplexy (loss of muscle control), hallucinations, sleep

paralysis.13/2/2015 7

OREXIN

Orexin, also called hypocretin, is a neurotransmitter that regulates arousal,

wakefulness and appetite. These are peptides found in the hypothalamus

involved in the regulation of sleep, energy homeostasis and autonomic functions.

Orexin was discovered in 1998 by two independent groups of rat-brain

researchers. One group named it as “OREXIN” derived from orexis meaning

appetite. The other group named it “HYPOCRETIN” because it is produced in the

hypothalamus and it resembles to secretin, a hormone found in the gut.

The brain contains the cells that produce orexin. In a human brain about 10,000

to 20,000 neurons in the hypothalamus produce orexin. Orexin-A and Orexin-B

are the active peptides derived from the prepro-orexin.

In particular orexins function in the maintenance and stabilization of sleep and

wakefulness and inhibition of REM sleep.

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Prepro-orexin Orexin (hypocretin)

Orexin constitute a novel peptide

family.

Orexin A/Hypocretin 1 is a 33 amino

acid peptide with N-terminal

pyroglutamyl residue and two

intrachain disulphide bonds.

Orexin B is a linear peptide of 28 amino

acids.13/2/2015 9

PHYSIOLOGICAL FUNCTIONS OF OREXINS

HEARTHeart rate↑↓

Blood

pressure↑↓

INTESTINES

Bicarbonate

secretion↑

Motility↑↓

STOMACH

HCl secretion↑

Motility↑↓

OVARIESReproduction↑↓

PANCREAS

Insulin

secretion↑↓

TESTISSpermatogenesis

↑↓

ADRENALS

Sympathetic

tone↑

Epinephrine

release↑

OREXINS

CNSWakefulness↑

Sleep↓

Food intake↑

Metabolic rate↑

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OREXIN RECEPTORS

The actions of orexins are

mediated via two types of GPCRs,

orexin 1 receptor (OX1R) and

orexin 2 receptor (OX2R).

OX1R couples to the Gq class of G-

proteins, which results in

activation of phosopholipase C

and subsequent triggering of the

phosphatidylinositol cascade.

OX2R couples to both Gq and Gi

classes of G-proteins in neuronal

cell lines.13/2/2015 11

DISTRIBUTION OF OREXIN RECEPTORS

OX1R and OX2R are widely distributed throughout the central nervous system.

OX1Rs are expressed in the prefrontal & infralimbic cortex, hippocampus , bed

nucleus of the stria terminalis (BST), anterior hypothalamus, dorsal raphe nucleus

(DR) & laterodorsal tegmental nucleus (LDT).

OX2Rs are also expressed in the amygdala, BST, DR. In addition to these regions,

OX2Rs are abundantly expressed in the dorsomedial hypothalamic nucleus,

hippocampus & medial septal nucleus.

The histological studies suggest that orexins and their receptors are likely to play a

broad regulatory role in the central nervous system and could regulate feeding,

sleep, emotion, and reward functions.

Additionally, OX1Rs are also distributed in peripheral tissues, such as the kidney,

adrenal gland, thyroid, testis, ovaries, and jejunum. OX2Rs are found in the adrenal

gland, lung, and pituitary.13/2/2015 12

DISTRIBUTION OF OREXIN RECEPTORS

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OREXIN ANTAGONIST

Sleep aids that target orexin action are known as “orexin receptor antagonists”

which means that they block the signaling of the chemical orexin in the brain.

Orexin plays a role in keeping people awake and alert, a medication that blocks its

action has the potential to promote sleep.

Eg : Almorexant, Suvorexant.

Mechanism of action of Orexin receptor antagonists

Orexin sleep aids affect different chemical system in the brain.

Many of the commonly prescribed sleep aids cause sleepiness by enhancing

GABA—a wide-reaching inhibitory neurotransmitter in the brain.

Orexin sleep aids block the brain’s receptors for the chemical orexin. Since they

target a more localized area of the brain, they will cause fewer side effects.

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COMPOUND ACT-078573(Almorexant)

MK-4305(Suvorexant)

MK-6096 SB-649868

COMPANY Actelion & GlaxoSmithKline

Merck & Co. Merck & Co. GlaxoSmithKline

CLINICAL TRIAL Phase III, discontinued

Phase III completed

Phase II completed Phase II completed

INDICATIONS Insomnia Insomnia Insomnia, migraine prophylaxis,

diabetic neuropathy.

Insomnia

T1/2 (HOURS) 21 12 NA 3-6

METABOLISM hepaticCYP3A4 (S/I)

hepaticCYP3A4 (S)

NA hepaticCYP3A4 (S/I)

DUAL OREXIN RECEPTOR ANTAGONISTS (DORA) IN DEVELOPMENT

S=substrate; I=inhibitor; NA=not available13/2/2015 15

SUVOREXANT

Suvorexant is another reversible dual orexin receptor

antagonist used in the treatment of insomnia.

Composition

The molecular formula for suvorexant is C23H23ClN6O2 .

The molecular weight is approximately 450.932 g/mol.

Mechanism of Action

Suvorexant is a potent dual orexin receptor antagonist

that blocks both OX1R and OX2R. It promotes sleep by

inhibition of orexin A and B neuropeptides that promote

wakefulness.

STRUCTURE OF SUVOREXANT

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Pharmacokinetics

Absorption: Well absorbed the onset of sleep

occurs 56 and 68 minutes after oral administration.

Distribution: Highly protein bound (99.5%).

Metabolism: Primarily metabolized by the

cytochrome P450 (CYP3A4) enzyme system.

Elimination: It is eliminated primarily via inactive

metabolites in the feces; there is no renal

elimination. The half-life is approximately 12.2

hours.13/2/2015 17

ALMOREXANT

Almorexant is a reversible, selective

dual OX1 and OX2 receptor antagonist.

Almorexant increases deep sleep and

REM sleep.

Commonly reported adverse effects in

the almorexant treated patients were

dizziness, nausea, fatigue, headache

and dry mouth.

Almorexant is discontinued due to

undisclosed human tolerability issues

STRUCTURE OF ALMOREXANT

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SB-649868

SB-649868 is a potent orally active orexin receptor antagonist.

It increases total sleep time (both nREM and REM sleep) and

reduces sleep latencies.

Compared to almorexant, the in vivo efficacy of this compound

is excellent.

Common side effects are headaches, dry mouth and

nasopharyngitis.

Side effects are dose dependent.

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The orexin antagonists improved both sleep initiation as

well as maintenance .

Orexin receptor antagonists are used for the management

of insomnia.

Still more clinical trails is to be carried out to know the

important pharmacological actions of Orexin receptor

antagonist.

CONCLUSION

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REFERENCES

Principles of anatomy and physiology (12th edition), Gerard J. Tortora and

Bryan H. Derrickson.

Neurobiology of Sleep and Wakefulness, Tom Scammell, MD Neurology,

BIDMC.

Sleep disorders. Babcock.ppt, www.mc.vanderbilt.edu.

Orexin and orexin receptors, Takeshi Sakurai.

The Role of Orexin/Hypocretin in the Central Nervous System and

Peripheral Tissues, Tomomi Tsunematsu and Akihiro Yamanaka.

Orexin receptor antagonists as therapeutic agents for insomnia Ana

C.Equihua1, AlbertoK.DeLaHerrán-Arita2 and ReneDrucker-Colin1.

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