Drugs Affecting Central Nervous System

Psychotherapeutic drugs

Hypnotics 12.1. Sleep cycles

Sleep is a cyclic phenomenon and has fundamental importance for body regeneration.

The following three phases of sleep have been defined:

 wakefulness  NREM sleep (nonrapid eye movements; slow-wave sleep – SWS)  REM sleep (rapid eye movements; paradoxic sleep – PS); REM sleep is associated with the mental activity of dreaming.

2 On the basis of EEG, slow-wave sleep has been divided into four stages: stage 1 – falling asleep, stage 2 – light sleep, stage 3 – medium-depth sleep, stage 4 – deep sleep. A normal adult enters sleep through NREM sleep. After approximately 90 minutes of NREM sleep the first REM sleep occurs, with a mean duration of about 20 minutes. NREM and REM sleep alternate cyclically through the night with the average length of the NREM-REM sleep cycle being approximately 90-120 minutes. REM sleep tends to be deepest in the last third of the night. A normal young adult displays a sleep pattern of 75–80% NREM and 20–25% REM sleep. 3 Both kinds of sleep are necessary for proper relaxation.

Stage 3 and 4 of NREM sleep and REM sleep are the most important for the process of regeneration. NREM sleep is important for energetic regeneration and thermoregulation. Psychic regeneration and consolidation of new memory engrams occur during REM sleep. Total lack of sleep is defined as . In the clinical sense insomnia is understood as a deficit of sleep or poor quality sleep, or both of these kinds appearing together. Insomnia results in psychic discomfort, anxiety and insufficient relaxation.

4 The causes of insomnia can be endogenic or exogenic. Very often endogenic depression is the cause of insomnia.

Somatic diseases that cause sleep disturbance are sleep apnea, hypertension and diseases accompanied by pain.

Shift work or rapid changes of time zones also influence the sleep cycle. For some patients insomnia is a disease in itself.

The incidence of insomnia is difficult to define, because most patients do not inform their physicians of this problem.

Insomnia can last several days (transient), up to 3 week (short-term) or over 3 week (chronic).

5 12.2. Sleep factors

There are several factors that modify sleep stage distribution.

 Catecholamines are involved in wakefulness and REM sleep.

1-Agonist (e.g. methoxamine) decrease REM sleep, while 1-antagonists increase REM sleep. Clonidine (primarily an 2-antagonist) is responsible for inducing sleep. However, it inhibits NREM sleep (stage 3 and 4).

The stimulation of dopamine D2 receptors promotes waking while blocking D2 receptors promotes sleep. Dopamine D1 receptors may be important for the regulation of REM sleep.

6  The serotonin agonists for 5-HT1 (via the 5-HT1A and 5-HT1B types at the hypothalamic level), 5-HT2 and 5-HT3 receptors cause wakefulness and inhibit sleep. Blockade of the 5-HT2 receptors (e.g by ritanserin) results in increased NREM and inhibition of REM sleep. It is believed that the 5-HT1A and 5-HT2 may be involved in sleep by regulation of sleep-promoting substances in the hypothalamus.  Histamine may play a role in wakefulness and REM sleep. The H1 receptor agonists and the H3 receptor antagonists increase wakefulness while the H1 receptor antagonists (e.g. diphenhydramine) and H3 receptor agonists have the opposite effect.  Acetylcholine, cholinergic agonists (bethanechol) and cholinesterase inhibitors are effective in the transition from NREM sleep to REM sleep.

7  The stimulation of the adenosine A1 receptors with adenosine produces a effect. It is thought that the hypnotic effect occurs via suppression of calcium efflux into presynaptic nerve terminals and decreasing the amount of neurotransmitters released into the synapse in brain regions critical for sleep. This apparent induction and maintenance of sleep is associated with increases in both NREM and REM sleep.  When the GABAergic interneurons are activated by an agonist, the monoaminergic structures of the brain stem are inhibited and because of that hypnotic activity is observed.  Melatonin is normally secreted during the night. Melatonin influence the circadian rhythm and sleep processes. Oral administration of melatonin is associated with a faster sleep onset and an increased total sleep time.

8 12.3. Classification of

 GABAA receptor agonists

. (, , , , ) . Imidazopyridines () . Pyrazolopyrimidines () . Cyclopyrrolones () .

9 12.3. Classification of hypnotics (2)

 Melatonin receptor agonists (melatonin, ramelteon)  Antihistamines and anticholinergics (diphenhydramine, doxylamine)  Antidepressants (trazodone, doxepin, and mirtazepine have been shown to be effective in the treatment of insomnia in patients with depression)  Herbal preparation (, German camomile, hops, passiflora)

10 Hypnotics disturb the relation between NREM and REM sleep. Sleep caused by hypnotics does not ensure full relaxation.

Pharmacologic treatment of sleep disturbance is effective in transient and short-term insomnia.

In chronic insomnia pharmacotherapy is used exclusively in the initial phase of therapy, and hypnotic drugs should be administered every three nights only.

11 Benzodiazepines

The benzodiazepines are used as daytime anxiolytics, sleep inducers, anesthetics, anticonvulsants and muscle relaxants. All benzodiazepines affect sleep stages. They increase total sleep and EEG fast activity and decrease nocturnal wakefulness, body movements, the number of awakenings, sleep latency (the time required to fall asleep) and stages 3 and 4 sleep (NREM).

12 Benzodiazepines act on the GABA system by increasing the inhibition function of GABA neurons. bind at benzodiazepine site of the GABAA receptor (ionotropic receptor connected with the chloride channel).

The binding of benzodiazepines with receptor enhances the affinity of GABA receptors for these neurotransmitters resulting in a more frequent opening of adjacent chloride channels. This in turn results in enhanced hyperpolarization and further inhibition of neuronal firing. Similarly, GABA agonists increase the binding of benzodiazepine derivatives with specific benzodiazepine site. The chloride channel modulated by GABAA receptors is 2,2,-heteropentamer.

13 The benzodiazepins do not bind to the GABA site and can only produce effects if presynaptic GABA has been released and is present at the receptors.

Benzodiazepins alloserically modulate the GABAA receptor, increasing the frequency of the chloride channel opening when GABA is bound, thus potentiating the response of exogenously released GABA.

14 Benzodiazepines

When the drug is stopped a gradual return to baseline values of NREM sleep is observed.

They also cause a mild suppression of REM sleep, especially during the first third of the night with a rapid return to baseline values when the drug is discontinued.

The use of a specific benzodiazepine as a hypnotic is based primarily on its pharmacokinetic properties. What makes administration of hypnotics unusual is that they are normally given as a single dose.

15 The following aspects are important for benzodiazepines used as hypnotics:

 acute tolerance developed to the benzodiazepine that diminish CNS effects before the drug is eliminated from the CNS  a very rapid redistribution of the benzodiazepine from the CNS to other tissues  a rapid drug elimination by the transformation and activity of metabolites.

The benzodiazepines that are specifically promoted as sleep inducers are estazolam, flurazepam, quazepam, temazepam, triazolam.

16 Hypnotics can be used over short (1 week), intermediate (2 weeks) and long periods of time (4 weeks or greater). A great majority of the benzodiazepines are effective for inducing and maintaining sleep when used initially or for a short time. When long-acting benzodiazepines with low receptor-binding affinity are used, a proper balance between pharmacodynamic and pharmacokinetic effects is very important.

For example, flurazepam and quazepam (long-acting hypnotics, t1/2 15-30 h and 7.5-15 h, respectively) are metabolized to active metabolites, which are slowly eliminated (t1/2 47-100 h).

17 A slow elimination of the active agent or active metabolites is responsible for their residual effects in the daytime. These effects may include “hangover” effects and over sedation and may be severe, especially in the elderly, even causing tremors, ataxia and confusion. Similar residual effects are observed when with moderately long elimination half-time (about 30 h) is used.

18 Newer benzodiazepines such as triazolam (an ultra-short acting hypnotic, t1/2 0.125-0.5 h, with high receptor-binding affinity) and temazepam (t1/2 15-30 h) are popular as sleep inducers, especially in elderly individuals. The following properties of the benzodiazepines and other hypnotics should be taken into consideration when they are used as hypnotics:  Benzodiazepines with long half-life should not be administered every day to avoid drug cumulation and the so-called vicious circle (rebound insomnia).  Benzodiazepines used over a long period of time cause drug tolerance and addiction.  In older individuals, the rate of biotransformation is decreased and sensitivity for benzodiazepines is increased. Because of that in these patients a dose of drug should be decreased (usually half a

normal dose). 19  Long-lasting administration of or flurazepam to older patients can cause memory disturbances similar to those found in Alzheimer’s disease.  BDA and other hypnotics act synergestically with , which also acts on the complex of the GABA-chloride channel receptor.  BDA and newer drugs such as zolpidem and inhibit the respiratory centre and cause muscle relaxation. These actions increase the risk of sleep apnea and can be one of the causes of increased mortality among individuals abusing hypnotics.  Pregnancy, lactation and certain diseases, e, g. depression, are contraindications for administration of hypnotics.

20 12.5. GABAA agonists

The nonbenzodiazepine GABAA agonists include

 zopiclone (cyclopyrrolone derivative),  zolpidem (imidazopyridine derivative) and  zaleplon (pyrazolopyrimidine derivative).

21 12.5.1. The mechanism of action

Zopiclone, zolpidem and zaleplon have been introduced as short- acting hypnotics. A GABA-A receptor, bound with the chloride channel consists of 5 subunits: two α, two β and one γ subunit. Within α, β and γ subunits the following subtypes are distinguished: α1–α6, β1–β3 and γ1–γ3.

Zopiclone and zolpidem bind with α1 subunit, whereas zaleplon with α1, α2 and α3 subunits. The binding of these drugs with α subunits facilitates the binding of GABA with γ subunits and increases the effects of its action – elongation of the opening time of the chloride channel, influx of chloride ions into cells and hyperpolarization of the cell membrane. The result of that is decreased nervous cell activity and hypnotic action. 22 12.5.2. Chemical structure and action

CH3 N 4 Zopiclone, IMOVANE, ZIMOVANE, XIMOVAN 1 N

O 6-(5-Chloro-2-pirydyl)-6,7-dihydro-7-oxo-5H-pirol[3,4-b]-pirazin-5-yl- O Cl 5 4-methyl-1-piperazinxcarboxylate N 2 5 6N N 1 7 N O Zopiclone, similarly to BDA, demonstrates hypnotic, anxiolytic, anticonvulsive and muscle-relaxing action. In a dose of 7.5 mg sedative-hypnotic action is dominant. In comparison with BDA, the anxiolytic action of zopiclone is weak.

Sedative-hypnotic action appears 20–30 min after administration and last 6–8 h. After oral administration zopiclon is rapidly resorbed (approx. 95% of the dose). The total bioavailability of zopiclone is approx. 80%. The half-time of elimination is 3.5–6.5 h and elongates in older patients 23 to approx. 8 h. Zopiclone is intensively metabolised. Zopiclone N-oxide (11%) is active, whereas N-demethylozopiclone (15%) and other metabolites, formed as hydrolysis and decarboxylation products, are inactive. Unchanged zopiclone and its metabolites are eliminated by the kidneys (approx. 80%) and intestines (approx. 16%). The half-time of elimination of active and inactive metabolites is shorter than that of zopiclone.

24 Zopiclone increases the activity of neuroleptics and drugs that block neuro-muscular transmission in an antipolarizing manner. Alcohol increases the activity of zopiclone, which can elongate reaction time. It is significant for drivers, machine operators and similar occupation.

When zopiclone has been overdosed, flumazenil (antagonist GABAA receptor) is used as an antidote.

25 N CH Zolpidem, BIKALM, STILNOX N 3 H3C O N,N,6-Trimethylo-2-p-tolylimidazo[1,2-a]-pyridine-3- N (CH3)2 acetamide

Zolpidem binds with α1 unit. Its affinity for α2 unit in the brain and the spinal cord and α3 unit in peripheral tissues is not high. This specific binding of zolpidem with α1 unit explains its dose-dependent sedative-hypnotic action and only slight muscle relaxation and anticonvulsive action. Its anxiolytic action is believed to be similar to that of the benzodiazepines. Zolpidem is well absorbed after oral administration. Its total bioavailability is approx. 70%. Its binding with plasma proteins is high (92%) but decreases in kidneys and liver insufficiency. The half-time of elimination from plasma is 2–5 h and elongates to approx. 10 h in older patients and those with severe liver damage.

26 Sedative-hypnotic action appears 20–30 min after administration and lasts 6–8 h and is similar to that of zopiclone. The therapeutic concentration in plasma is 80–150 ng/ml. Toxic symptoms are observed at a concentration of 0.5 mg/ml of plasma.

Flumazenil removes such intoxication symptoms as breath depression and vision disturbance. An indication to use zolpidem is insomnia. It should not be used together with psychotropic drugs and opioid analgesics.

Zolpidem is contraindicated for similar reason as zopiclone.

27 Zolpidem is intensively metabolized in the liver. Oxidation of the methyl group and hydroxylation of the ring lead to inactive metabolites, which are eliminated by the kidneys (approx. 56%) and intestines (approx. 37%).

N Dehydrogenaza N CH3 CH3 N alkoholowa N H2C HOOC O O HO N(CH3)2 N(CH3)2

CYP3A4

N HO N CH3 CH3 N H3C N H3C O O

N(CH3)2 N(CH3)2 CYP3A4

N N Dehydrogenaza CH2 OH COOH N H3C alkoholowa H3C N O O

N(CH3)2 N(CH3)2 28 CH3 N CH3 Zaleplon, SONATA 1 3 O 3-(3-Cyanopyrazol[1,5-a]pyrimidin-7-yl)phenyl-N-ethylacethamide

N 7 N 1

3 N CN UDPGA

Zaleplon binds with α , α and α aldehyde oxidase 1 2 3 Zaleplon subunits. 5-Oxo-zaleplon Its action time is short (approx. 4 h). CYP 3A4 aldehyde oxidase During the use of zaleplon, tolerance Deethylozaleplon 5-Oxo-deethylzaleplon and withdrawal symptoms have not UDPGA been observed. Zaleplon is metabolized by aldehyde oxidase and CYP3A4.

The metabolites of zaleplon are inactive. Its biological half-life is approx. 2 h.

29 12.6. Barbiturates

Barbituric acid was first synthesised in 1864 by A. von Baeyer (the 1905 recipient of the Nobel Prize for Chemistry). The first barbituric acid derivative used in therapy was Veronal (at present ) synthesised by E. Fischer (also a Nobel Prize laureate) in 1903. Because of their hypnotic properties, many barbituric acid derivatives have been introduced into therapy. Until the 1960s the barbiturates were the greatest group of sedative and hypnotics agents. At that time, they began to lose their dominant position to the benzodiazepines.

30 12.6.1. The mechanism of action

At therapeutic doses the barbiturates enhance GABAergic inhibitory response, in a mechanism similar to that of the benzodiazepines (by influencing conductance at the chloride channel). They act on the complex of the GABA receptor by bonding with the binding site (different from that of the benzodiazepines) in a β subunit. The reaction of the ligand (BARB) with the receptor elongates the opening-time of the chloride channel, which results in the influx of chloride ions into cells, hyperpolarization of the cell membrane and reduces cell excitation.

31 At higher concentrations, the barbiturates can increase GABA-A- mediated chloride ion conductance and enhance both GABA and benzodiazepine binding.

Therefore, the barbiturates and benzodiazepines display cross- tolerance and this can be seen with the barbiturates exhibiting weak anxiolytic and muscle relaxant properties. At higher concentrations the barbiturates also reduce glutaminergic transmission. The sedative, hypnotic, anticonvulsive and analgetic action of the barbiturates is partially caused by their action on the adenosine system.

32 12.6.2. Chemical structure

Barbituric acid and its monosubstituted derivatives are strongly ionized and they do not demonstrate biological activity.

The following are used in therapy:

 5,5-disubstituted barbituric acid derivatives  1,5,5- trisubstituted barbituric acid derivatives  5,5- disubstituted thiobarbituric acid derivatives

H CH3 H O N O O N S 1 O N O 6 2 1 6 2 R1 5 3 R1 4 N H R 5 NH 1 4 3N H R2 R R2 2 O O O 33 5,5- Disubstituted barbituric acid derivatives

H O N O 6 1 2 R = R = H; Barbituric acid R 5 1 2 1 4 3N H R2 (1H,3H,5H)-pyrimidine-2,4,6-trion = Hexahydropyrimidine-2,4,6-trion O

R1 = - CH2-CH3

R2 = CH2-CH3, Barbital R2 = -CH2-CH2-CH2-CH3, R2 = -CH(CH3)-CH2-CH3, Secbutabarbital, BARBITAB R2 = -C(CH3)=CH-CH2-CH3, , DELVINAL

R2 = -C6H5, Fenobarbital, LUMINALUM

R2 = , CYCLOBARBITALUM

R2 = -CH(CH3)-CH2- CH2-CH3, , PENTOBARBITAL 34 H O N O 6 1 2 R 5 1 4 3N H R2 O

R1 = -CH2-CH=CH2

R2 = -CH2-CH=CH2, , ALLOBITAL R2 = -CH(CH3)2, , APROTAL, NUMAL R2 = -CH(CH3)-CH2-CH2-CH3, , SECONAL

R1 = -CH=CH2

R2 = -CH(CH3)-CH2-CH2-CH3, , OPTANOX

R1 = -CH3

R2 = -C6H5, , RUTONAL

35 1,5,5- Trisubstituted barbituric acid derivatives

R1 = - CH2-CH3 R = -C H , , PROMINAL CH3 2 6 5 O N O 1 6 2 R 5 R1 = -CH3 1 4 3N H R2 O R2 = , NARCOSANUM

R1 = -CH2-CH=CH2

R2 = -CH(CH3)-CC-CH2-CH3, , BRIETAL

36 5,5- Disubstituted thiobarbituric acid derivatives

H O N S R = - CH -CH R 1 2 3 1 NH R2 = -CH(CH3)-CH2-CH2-CH3, Thiopental, THIOPENTAL R2 O

37 H O N O 12.6.3. The chemical structure-activity 6 1 2 R 5 1 4 3N H R2 relationship O The substituents in positions 1 and 5 increase the lipophilicity of the compound, which affects its binding with proteins as well as the rate and time of action. The influence of substituents on lipophilicity, binding with adenine, the rate and time of action:

 Disubstituted barbiturates form dimers with adenine, which are characterized by a relatively high association constant.  Disubstituted barbiturates containing simple, saturated

subsituents (e.g. –C2H5; barbital) at C5 demonstrate long but not very strong action.  The presence of a double bond in substituents (allyl, vinyl) shortens the time of action and enhances it. 38  Asymmetrical 5,5-disubstituted barbiturates demonstrate the most effective action when the number of carbon atoms in both substituents is 5–8.  The branching of a substituent shortens the time of action. In branched substituents the greatest increase of lipophilicity is observed when the methyl group appears at the C1 atom bound with the hexahydropyrimidinetrione ring.  1,5,5-Trisubstituted barbiturates form dimers with adenine, which are characterized by an association constant lower than that of 5,5-disubstituted barbiturates (20% of that value). Trisubstituted derivatives demonstrate lower acidity and greater lipophilicity. In addition to the accelerating and shortening of action, these changes strengthen activity from hypnotic to anesthetic.

39 Action and application

The barbiturates have a different pharmacologic profile from that of the benzodiazepines. They exert a depressant effect on the cerebrospinal axis and depress neuronal activity as well as skeletal muscle, smooth muscle and cardiac muscle activity. Depending on the compound, dose and route of administration, the barbiturates can produce different degrees of CNS depression and have found use as sedatives, hypnotics, anticonvulsants or anesthetics.

40 Currently, the barbiturates are rarely used as sedatives and hypnotics because of their higher toxicity. This is associated with their ability to cause greater CNS depression and their ability to induce many of the liver drug metabolizing enzymes. In addition, the barbiturates cause drug tolerance and often drug dependence. In spite of these disadvantages, the barbiturates are occasionally used as sedatives and hypnotics.

Long-acting barbiturates have this application but they are less safe than the benzodiazepines. However, the barbiturates are primarily used as anesthetic and antiseizure drugs. In the treatment of epilepsy derivatives containing a phenyl substituent () are used due to their anticonvulsive action. The barbiturates with short and strong-action (e.g. thiopental) are used for premedication in anesthesia. 41 Adverse effects

Long-lasting administration of barbiturates leads to drug tolerance and addiction. The symptoms of chronic intoxication involve:

 psychic disturbance  disturbed function of the vegetative system  allergic reactions  the damage of the parenchymatous organs (e.g. the kidneys, lungs, liver, spleen, brain). Barbiturates administered in large doses cause death because of the inhibition of the respiratory and circulatory systems. The barbiturates demonstrate interaction with drugs acting depressively on the CNS. As the inductors of microsomal enzymes they accelerate the metabolism of certain drugs (e.g. anticoagulants) and decrease their efficacy. 42 H N

COOH L-Tryptophan Melatonin Tryptophan hydroxylase NH2 Melatonin is synthesised in the pineal H gland and in the retina. Its secretion is N controlled by the suprachiasmatic nucleus HO COOH 5-Hydroxytryptophan

(SCN) and follows to an endogenous Aromatic NH2 amino acids circadian rhythm. decarboxylase

The precursor in the 4-stage biosynthesis H N of melatonin is L-tryptophan. 5-Hydroxytryptamine HO 5-HT (Serotonin) The reaction of N-acetylation, catalysed NH2 Ac-CoA by 5-HT N-acetylotransferase (NAT), is 5-HT N-acetylotransferase critical for the rate of melatonin CoA = NAT biosynthesis. NAT is an inductive enzyme H N N-Acetyl- 5-HT dependent on the intracellular HO 2+ concentration of cAMP and Ca ions. Hydroxyindole O N O-methyltransferase H Melatonin synthesised in the pineal gland CH3 is released pulsatively into the blood and H N cerebrospinal fluid and in this way it is MELATONIN H3CO transported to different tissues, where it O N 43 H demonstrates its action. CH3 The inactivation of melatonin occurs in the liver and involves hydroxylation of the indole ring at position 6 and coupling 6-hydroxymelatonin with active glucuronic acid (UDPGA) or sulfuric acid (PAPS). The metabolites are eliminated in urine. A small amount of melatonin is transformed in the brain to Nγ-acetyl- N-formyl-5-methoxynurenamine.

44 The biosynthesis of melatonin follows the circadian rhythm depending on lighting. The level of melatonin and NAT activity are the greatest at night. In vertebrates 3 profiles of the night-time production of melatonin are distinguished. In humans (profile B) an increase in the melatonin concentration begins in the late evening.

A maximal concentration is observed between 2 and 3 in the morning. Then the concentration of melatonin slowly decreases to the day-time level, which is reached by daybreak. The elongation of the night during winter prolongs increased melatonin levels.

The concentration of melatonin is positively corelated with the length of the night.

45 The rhythmic production of melatonin in the retina is independent from its synthesis in the pineal gland and is controlled by the photoreceptor cells of the retina. Light is the most important factor of the external environment which regulates the biosynthesis of melatonin. In mammals the information about light reaches the pineal gland by the polyneuronal pathway. The increase of postganglionic sympathetic fibre activity at night causes the release of noradrenaline (NA).

The stimulation of 1 receptors by NA leads to an increase in the cAMP concentration, which triggers a cascade of biochemical reactions (some still not explained) leading to NAT induction and the increase of melatonin synthesis. The stimulation of 1 receptors by NA enhances the action resulting from the stimulation of 1 receptors.

Apart from a suppressive effect, light also influences the circadian rhythm of melatonin biosynthesis. 46 The third feature of the melatonin-producing system is a gradual decrease in the amplitude of the melatonin circadian rhythm, progressing with age. In humans before approx. the 12th week of life no difference between day and night melatonin levels in the blood is observed. Increased night production of melatonin occurs between the fourth month and 3- 5 years of life. During the next 10–12 years the melatonin level sharply decreases.

47 A mild decrease of melatonin levels is observed until age 40–50. In individuals over 65 years of life, low-amplitude circadian rhythm of melatonin levels in body fluids is noticed.

Changes of this type are also observed in Alzheimer patients. It is believed that the age-linked decrease in melatonin production is caused by morphologic changes in the pineal gland, reduced number of adrenergic 1 receptors in pinealocytes, diminished amount of cells in the suprachiasmatic nucleus of the hypothalamus and desynchronisation of these structures, which constitute the biological clock.

48 Melatonin shows biological activity after binding with specific melatonin membrane receptors, MT1 and MT2. Two subtypes of MT1 receptors are known – MT1a and MT1b. Both are coupled with G protein. Melatonin receptors are coded by different genes and have a different composition of amino acids.

In humans, the gene for MT1a receptors is on chromosome 4q35.1, whereas the gene for MT1b receptors on chromosome 11q21–22, which is in the same region of the genome as the gene for dopamine

D2 receptors.

The degree of homologation (similarity) between the amino acids of

MT1a and MT1b receptors is 60%, whereas the degree of homologation between the same subtypes of receptors in different mammals is 80%. Homologation is higher in the membrane region.

49 Melatonin and its derivatives are the strongest melatonin receptor agonists 2-iodomelatonin 6-chloromelatonin melatonin > hydroxymelatonin (metabolite) > 6-methoxymelatonin. The precursors in the biosynthesis of melatonin show very weak affinity (N-acetyl-5-HT) or do not show any affinity (L-tryptophan and 5-HT) for melatonin receptors. Melatonin metabolites, except 6(OH)- melatonin, are inactive.

Melatonin receptors are found in various regions of the brain. There are small amounts of melatonin receptors also in peripheral tissues such as intestines, ovaries and blood vesels. In the brains of mammals melatonin receptors exist mainly in the suprachiasmatic nucleus and in the tubercular part of the hypophysis.

A smaller number of melatonin receptors is found in the retina, paraventricular nucleus, cerebral cortex and hippocampus. 50 It is believed that the tubercular part of the hypophysis plays a key role in the regulation of season-linked physiologic processes by melatonin, whereas the suprachiasmatic nucleus of the hypothalamus is responsible for the regulation of the circadian rhythm. Nonneuronal melatonin receptors in the hypophysis can influence reproductive functions. It is also possible that cardiovascular functions and body temperature is controlled by peripheral receptors in the arteries.

The binding of melatonin with

 MT1 receptors, characterized by greater sensitivity, activates adenine cyclase, which catalyses the biosynthesis of cAMP

 MT2 receptors, characterized by lower sensitivity, stimulates the hydrolysis of phosphatidylinositol.

51 Melatonin also acts intracellularly. In cytosol, it binds directly with calmodulin and regulates the activity of this specific enzyme. Melatonin is probably the ligand for nucleic Z-retinoid alpha and beta receptors.

Melatonin can also neutralize free radicals, which results in the protection of macromolecules, especially DNA, from their oxidative action. However, this protective action is only observed at melatonin concentrations greater than those observed at night. The reduction of the night release of melatonin may be a cause of aging. Melatonin is probably responsible for the inhibition of tumor growth by the increasing immunological response. It has been shown that melatonin stimulates the production of IL-4 in T helper cells in mice. Melatonin can protect from dying bone marrow cells damaged by toxic substances.

Melatonin is one of the fundamental factors controlling the circadian sequence, mainly the sleep-wakefulness rhythm. It is believe that the disturbance of circadian rhythm of melatonin biosynthesis can be one of the causes of chronobiological sleep disturbances. At present, these disturbances are the only clinically documented indications to use melatonin.

52 As a neurohormone, melatonine is a poor drug because of its poor absorption, low oral bioavailability (<10%), rapid first-pass metabolism by CYP1A2 to 6-hydroxymelatonin (its primary metabolite), and ubiquitous effects. The analogue of melatonin - Ramelteon - as a very potent and very selective ligand for the MT1 receptor, with superior in vivo activity and safety profile for use in the treatment of insomnia.

Ramelteon binds primarily with the melatonin MT1 receptor and does not bind with other receptors associated with sleep (e.g.,

GABAA, dopamine, or opiate receptors). S-Enantiomer shows approximately 500-fold greater affinity than R-isomer for this receptor.

Its greater selectivity for human MT1 receptor is consistent with its ability to primarily shorten sleep onset rather than to readjust the circadian rhythm. 53 Ramelteon is rapidly absorbed OH OH H H H H and undergoes extensive first-pass N N metabolism with an oral O O O bioavailability of less than 2% and O O an elimination half-life of Major CYP1A2 approximately 2 hours. H H N Metabolism is primarily O Ramelteon hydroxylation of the propionamide O side chain to an active metabolite. Additional oxidative metabolism CYP3A4 by the CYP enzymes occurs on the H H H H N N Esterase indane ring and the dihydrofuran O O ring to form a lactone ring and O O O O OH esterase hydrolysis of the lactone H to a carboxylic acid. These metabolites are inactive. 54 Ramelteon has been shown to be effective in initiating sleep (shortening sleep latency) but not in maintaining sleep.

In contrast to the GABAA agonist drugs, ramelteon does not depress cognitive function, memory, or ability to concentrate at normal doses. Ramelteon does not appear to have any abuse liability.

55 H O N CH3 O

Tasimelteon is used in sleep disordes caused by the change of time zones or by shif work.

It is a selective agonist for the melatonin receptors MT1 and MT2 in suprachiasmatic nucleus of the brain, similar to ramelteon.

56 Agomelatine The chemical structure of agomelatine is very similar to that of melatonin. Thus melatonin contains an indole part, whereas agomelatine has a naphthalene bioisostere instead. Agomelatine

Agomelatine is a agonist for the melatonin receptors MT1 and MT2, and in greater concentration – antagonist for receptors 5-HT2B and 5-HT2C. Agomelatine is used in therapy of depression with sleep disordes.

57 Problems

Long-lasting administration of diazepam or flurazepam to older patients can cause memory disturbances similar to those found in … disease.

In older individuals, the rate of biotransformation is … and sensitivity for benzodiazepines is … .

Benzodiazepines used over a long period of time cause drug … and … .

58 Problems

Long-lasting administration of diazepam or flurazepam to older patients can cause memory disturbances similar to those found in … disease.

In older individuals, the rate of biotransformation is … and sensitivity for benzodiazepines is … .

Benzodiazepines used over a long period of time cause drug … and … .

59 Problems

[…] has been shown to be effective in initiating sleep (shortening sleep latency) but not in maintaining sleep. It does not appear to have any abuse liability.

[…] is used in sleep disordes caused by the change of time zones or by shif work.

[…] is used in therapy of depression with sleep disordes.

60 Problems Barbiturates act on the complex of the GABA receptor by bonding with the barbiturate binding site (different from that of the benzodiazepines) in a … subunit. The reaction of the ligand (BARB) with the receptor elongates the opening-time of the … channel, which results in the influx of chloride ions into cells, … of the cell membrane and reduces cell excitation.

Long-lasting administration of barbiturates leads to …

In the treatment of epilepsy derivatives containing a phenyl substituent (….) are used due to their anticonvulsive action.

The barbiturates with short and strong-action (e.g. thiopental) are used for … . 61 Which of the following formulas is correct for

a) Phenobarbital b) Tasimelteon c) Thiopental d) Zaleplon

H CH3 O N S N CH R 3 H 1 NH 1 O N O 3 O H R O N H C 2 3 NH O CH3 N O 7 N 1 O R1 = - CH2-CH3 3 R = -CH(CH )-CH -CH -CH N 2 3 2 2 3 CN

1. 2. 3. 4.

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