- Email: [email protected]
New perspectives for the treatment of disorders of sleep and arousal
© 2007. Elsevier Masson SAS. Tous droits réservés
Ann Pharm Fr 2007, 65 : 268-274
Médicaments du sommeil et de la vigilance New perspectives for the treatment of disorders of sleep and arousal D.J. Sanger, C. Soubrane, B. Scatton, Summary. A variety of molecules with novel mechanisms of
Résumé. Différents types de molécules ayant un nouveau
action are currently being evaluated for their potential as treat-
mécanisme d’action sont actuellement evalués dans le traite-
ments for sleep disorders. The GABA-A receptor complex
ment des troubles du sommeil. Bien que le complexe GABA-
remains an important target for hypnotic drugs (eg gaboxadol,
A demeure une cible essentielle pour les agents hypnotiques
indiplon). However, drugs acting through histamine, calcium
(gaboxadol, indiplon), d’autres mécanismes d’action impliquant
channels and serotonin receptors may also be of interest for
les récepteurs histaminiques ou sérotoninergiques ou encore
the treatment of insomnia. In the case of the 5HT2A subtype
les canaux calciques pourraient également être une voie inté-
of serotonin receptors, several molecules which improve sleep
ressante dans le traitement de l’insomnie. Plusieurs molécules
maintenance and modify sleep architecture by increasing slow
qui bloquent les récepteurs sérotoninergiques de type 5HT2A
wave sleep are currently being tested (eg eplivanserin). Two
et qui maintiennent le sommeil et modifient son architecture
new drugs with efficacy in excessive sleepiness (modafinil,
en augmentant sa composante lente sont actuellement en
sodium oxybate) have improved the treatment of this condition.
développement clinique (ex, eplivanserin). Dans le cas de la
However, the mechanisms of action of these agents are poorly
somnolence diurne excessive, deux nouveaux produits (moda-
understood. The recent discovery of the hypocretin arousal sys-
finil et oxybate de sodium) sont récemment venus améliorer
tem in the hypothalamus may aid the identification of additional new drugs. An agonist at receptors for the pineal hormone melatonin is available in some countries (ramelteon) but is currently used only for the treatment of insomnia associated with difficulties of sleep onset. Additional melatonin receptor agonists are being developed and may have potential for treating several conditions including circadian rhythm disorders and depression.
les possibilités thérapeutiques. Leur mécanisme d’action demeure toutefois inexpliqué. La découverte récente du système excitateur hypocrétine au niveau de l’hypothalamus pourrait faciliter l’identification de nouvelles molécules. Un agoniste des récepteurs de la mélatonine (ramelteon) est commercialisé dans certains pays pour le traitement des troubles de l’endormissement seulement. D’autres agonistes des récepteurs de la mélatonine en cours de développement pourraient avoir un potentiel thérapeutique dans plusieurs indications, dont les troubles des rythmes circadiens et la dépression. Mots-clés : Insomnie, Vigilance, Sérotonine, GABA, Mélatonine.
Key-words: Insomnia, Arousal, GABA, Serotonin, Melatonin.
Nouvelles perspectives dans le traitement des troubles du sommeil et de la vigilance. D.J. Sanger, C. Soubrane, B. Scatton. Ann Pharm Fr 2007 ; 65 : 268-274.
Sanofi-Aventis Recherche, 31, avenue Paul Vaillant-Couturier, F 92220 Bagneux. Présentation devant les Académies nationales de pharmacie et de médecine, lors d’une séance commune, le 29 novembre 2006, à l’École du Val-de-Grâce, Paris. Correspondance : D.J. Sanger, à l’adresse ci-dessus. E-mail : [email protected]
268
New perspectives for the treatment of disorders of sleep and arousal
Insomnia Insomnia, consisting of problems in initiating sleep, maintaining sleep and non-restorative sleep, is common, and, in some patients may be chronic and disabling. Although sleep hygiene advice may be very useful and psychological techniques such as cognitive behavioural therapy have been found helpful in alleviating this condition, drug therapy remains the most convenient treatment. The older, barbiturate “sleeping pills” were largely replaced as the treatment of choice by the much safer benzodiazepines such as temazepam and triazolam some years ago. However, benzodiazepines themselves have been considered to have a number of undesirable effects and the more recently introduced molecules zolpidem, zopiclone and zaleplon are more appropriate for many patients [1]. Benzodiazepines exert their pharmacological effects by binding to a specific binding site (the BZ receptor) which forms part of the macromolecular receptor complex known as the GABA-A subtype of receptors for the brain’s major inhibitory neurotransmitter gamma-hydroxy-butyric acid (GABA). Molecules such as the benzodiazepines which act as agonists at BZ sites potentiate the effects of the transmitter and in this way exert their sedative/hypnotic and other pharmacological actions. Zolpidem, zopiclone and zaleplon also act at BZ sites associated with GABA-A receptors. However, zolpidem and zaleplon have selectivity for a certain sub-population of these receptors containing alpha1 subunits and zopiclone, while not showing receptor subtype selectivity, may bind to BZ receptors in a manner different from that shown by benzodiazepines. These differences probably explain the pharmacological and clinical differences from traditional benzodiazepines [2, 3]. GABA-A receptors as a target for development of new drugs Most past and present hypnotic drugs exert their therapeutic actions through GABA-A receptors (at least some of the effects of barbiturates and ethanol are also produced by enhancing GABAergic activity), and these receptors remain an important target for new hypnotic drug discovery and deve-
Table I. — New Hypnotic Drugs Acting at the GABA-A Receptor Complex Currently in Clinical Development Nouveaux agents hypnotiques agissant sur le complexe GABA-A actuellement en développement clinique. Drug
Mechanism
Gaboxadol
Active at receptors with alpha4 and delta subunits. Selective for extrasynaptic receptors
Indiplon
BZ receptor agonist with selectivity for receptors with alpha1 subunits
NG2-73
BZ receptor partial agonist
EVT-201
BZ receptor partial agonist
lopment [4]. Table I lists four novel molecules currently being tested as potential hypnotics. Gaboxadol and indiplon are in late stage and NG273 and EVT-201 in earlier stage clinical trials. Gaboxadol is a relatively old compound, previously know as THIP, which reached clinical testing for several disorders including pain and epilepsy. However, although never brought to the market, it was found to have sedative properties, thought undesirable at the time. When it was also shown to produce effects on sleep architecture quite different from those of older hypnotics, the idea of testing gaboxadol as a potential treatment for insomnia was born. Benzodiazepines are clearly effective in inducing and maintaining sleep but tend to produce light sleep and even decrease the proportion of deep, slow wave sleep. In contrast, gaboxadol produces a substantial increase in slow wave sleep in both experimental animals and humans. It is not known whether this, in itself, can lead to clinical benefits in patients suffering from insomnia. However, clinical trials are currently underway and should help to define whether the molecule could have advantages over the currently available drugs [5]. The manner in which gaboxadol modulates GABA-A receptor function also differs from those of benzodiazepines and other hypnotics. Gaboxadol does not bind to the BZ site but has been shown to have selectivity for GABA-A receptors containing delta subunits. These receptors seem to be particularly dense in the thalamus, a brain region often associated with the control of sleep, and are found on neural membranes situated outside synaptic areas. The biology of these extra-synaptic
269
D.J. Sanger et Coll. receptors has been subject to considerable research in recent years and it seems that they modulate synaptic transmission and neuronal excitability in a way different from receptors found within the synapses [6]. It is possible, therefore, that gaboxadol will show clinical differences from older drugs in patients with insomnia1. Indiplon is a derivative of zaleplon and has a similar pharmacological profile including selectivity for GABA-A receptors containing alpha1 subunits [7]. Like gaboxadol, it is currently being tested in a range of clinical trials in insomniac patients but only brief descriptions of the results have thus far been published. A novel aspect of indiplon’s development is that two pharmaceutical forms are being tested having immediate release and modified release characteristics. It is hoped that this will allow for treatment of a wider range of patients with forms of insomnia (see below). NG2-73 and EVT-201 both bind to BZ sites and have the unusual characteristic of being partial agonists. This indicates that, even when they occupy a large proportion of available receptors they do not stimulate the same degree of receptor output as full agonists. In pharmacological tests in vitro and in vivo procedures in experimental animals, compounds characterized as partial agonists produce anticonvulsant and anxiolytic-like effects without sedation. Several such molecules reached the clinic in the hope that they would be effective treatments for anxiety but, unlike most other anxiolytics, would not produce the side effect of sedation. Unfortunately, all such development programmes have failed and it has been found that BZ receptor partial agonist do indeed produce sedation in humans [8]. It will therefore be particularly interesting to see whether NG273 and EVT-201 are shown to be useful treatments for insomnia and, particularly, whether they have any advantages over the BZ receptor full agonists already available. New Pharmaceutical Forms. It has become increasing clear that not all forms of insomnia are the same and that different patients may best benefit from drugs with different pharmacological or pharmacokinetic characteristics. Some years 1
Note added in proof: the development programme for gaboxadol has recently been discontinued.
270
ago it was realized that many older hypnotic drugs had elimination half-lives and durations of actions which were too long, leading to impaired performance in the morning. This led to the development of drugs such as zolpidem which has a rapid onset and short duration of action (elimination half-life of approximately 2.5 hours). However, in some patients with particular problems of sleep maintenance with frequent waking in the middle or later sections of the night, zolpidem was deemed to be too short acting. A modifed release form of the drug was therefore developed and is now available in several countries [9]. Zolpidem-MR consists of a tablet with a biphasic pattern of release of the active drug. It has been shown to be particularly effective in reducing time awake during the middle of the night in patients with chronic insomnia [10]. As noted above, a potentially similar modified release form of indiplon is also being tested and plans have been reported for the development of a modified release form of zaleplon. Several other pharmaceutical forms of zolpidem, mostly aiming at more rapid release and buccal absorption have also been described but only preliminary data seem so far to be available. Serotoninergic drugs It has been known for many years that neural pathways utilizing serotonin as their primary neurotransmitter play important roles in the control of sleep states. However, drugs which modulate serotoninergic transmission by, for example, stimulating or blocking receptors for this transmitter, have never found clinical use in the treatment of insomnia. This may soon change as several agents with selective activity as antagonists or inverse agonists at the 5HT2A subtype of serotonin receptors are currently being tested in patients with sleep disorders (fig. 1). 5HT2A antagonists do not show pharmacological effects similar to traditional sedative/hypnotic agents — they do no reduce the latency to fall asleep, for example. However, they do modify sleep architecture by selectively increasing slow wave sleep [11]. Table II shows some data from a study in which the 5HT2A antagonist eplivanserin was found to induce a major increase in slow wave sleep in healthy volunteers without affecting other sleep parameters. Preliminary evidence from studies of patients with insomnia have shown that eplivanserin as well as other
New perspectives for the treatment of disorders of sleep and arousal Table II. — Effects of Eplivanserin on Sleep Parameters in Healthy Subjects. Effets de l’Eplivanserin sur les paramètres du sommeil des volontaires sains.
Pruvanserin O
HN
N
Placebo
Eplivanserin 1 mg
Sleep Latency
11,8
15,8
TST
441
450
REM
97,7
85,6
SWS
8 202
143,8*
All values are in minutes. TST: total sleep time, REM: rapid eye movement (paradoxical) sleep, SWS: slow wave sleep (stages 3 and 4). * p<0.001 difference from placebo. Data are taken from Landolt et al (2006) and show sleep parameters recorded in 10 subjects over a 10 hour overnight period. Toutes les valeurs sont exprimées en minutes. TST : total sleep time, REM : rapid eye movement (sommeil paradoxal), SWS : slow wave sleep (stades 3 et 4). Différence versus placebo * p < 0,001. Données de Landolt et al (2006) montrant les valeurs des parameters du sommeil enregistrés sur dix heures au cours de la nuit chez dix sujets.
N
N
F
Eplivanserin
F O N
N
HO
molecules with a similar mechanism of action can also increase deep sleep in this population and, in addition, can improve sleep maintenance and sleep quality. If clinical testing continues to be successful, such molecules may eventually become available for patients with disturbed sleep but who do not suffer from difficulties of sleep initiation.
Volinanserin OH
O O
N
Other mechanisms Another group of molecules which have been reported to modify sleep architecture without decreasing sleep onset latency are derivatives of the antiepileptic drugs gabapentin and pregabalin. These molecules appear to act selectivity on the alpha2-delta calcium channel and may have potential in treating sleep disorders [12]. Molecules with antihistaminergic effects are well known to produce sedation and some have been used as sleep aids [12]. This is despite the fact that modern, well-controlled clinical trials have never been described. However, histamine is a neurotransmitter involved in the control of sleep and wakefulness, and it is considered that novel compounds with selective antagonist activity at the H1 receptor subtype may have potential in treating insomnia. The old antidepressant agent doxepin acts at several transmitter systems
F
Figure 1. Chemical structures of three selective 5HT2A antagonists currently being tested in the clinic for their potential in the treatment of insomnia. Pruvanserin was previously known as EMD-281044, eplivanserin as SR-46349 and volinanserin as M100907 Structures chimiques de trois agonistes 5HT2 actuellement testés en clinique pour leur potentiel thérapeutique dans l’insomnie. Pruvanserin, eplivanserin et volinanserin étaient préalablement connus respectivement sous les codes EMD-281044, SR-46349 et M100907.
but has particularly high affinity for H1 receptors. It has been suggested, therefore, that doses of this drug considerably lower than those used to treat depression may be considered selective H1 antagonists. Such doses are currently being tested in patients with insomnia [14]. Preliminary descriptions of the results of these trials suggest
271
D.J. Sanger et Coll. good efficacy, particularly on measures of sleep maintenance. Another selective H1 antagonist, HY- 12075 is also in early clinical testing.
Problems of decreased arousal Although the number of patients suffering from hypersomnias and requiring treatment to increase arousal is certainly smaller than those with insomnia, they nevertheless represent a significant population. The relatively rare condition of narcolepsy, for example, is characterized by cataplexy and daytime sleepiness and, until recently, was treated with psychomotor stimulant drugs such as amphetamines. There are also large numbers of patients who have problems of daytime sleepiness produced by medical conditions such as obstructive sleep apnea or fibromyalgia, or disrupted rhythms of life which lead to disturbed sleep, including night work and international travel. Treatment of problems of excessive sleepiness will probably be considerably improved by several recent advances in basic research and drug development. Modafinil This drug is a novel molecule with wake-promoting effects [15]. It does not produce the same psychomotor stimulation and euphoria as drugs such as the amphetamines and is therefore considered to have little potential to lead to abuse or dependence. Currently, modafinil is used to treat daytime sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnoea and shift work. It has been shown to have clear but modest efficacy in these conditions and is generally well tolerated. Modafinil provides an undoubted step forward in the treatment of excessive sleepiness and might be expected to point the way for new drug discovery programmes aimed an identifying yet more efficacious drugs. Unfortunately, however, despite considerable research, the mechanism of action of the drug is still very poorly understood. It seems that modafinil may act primarily at hypothalamic pathways involved in the control of wakefulness but the exact neurotransmitter or other neuropharmacological mechanism involved has yet to be identified. Roles for dopamine, noradrenaline, GABA, glutamate and orexin, among other neu-
272
rotransmitters, have been proposed but it remains to be determined which, if any of these systems plays the main part in modafinil’s clinical actions [16]. Sodium oxybate Another agent with clinical efficacy in the treatment of excessive sleepiness but whose mechanism of action is not well understood, is sodium oxybate [17]. Sodium oxybate is the sodium salt of gamma-hydroxybutyrate (GHB) and is used for the treatment of patients with narcolepsy and improves both daytime sleepiness and cataplexy. Clinical studies also indicate that it may have potential for the treatment of excessive sleepiness associated with other conditions such as fibromyalgia. GHB is an endogenous substance, found in the brain, and is a metabolite of GABA. It was first synthetised in the 1960’s by H Laborit and the pharmacological properties of endogenous administered GHB have been extensively investigated. In addition to sleep promoting actions a variety of other effects including anaesthesia and analgesia have been described and GHB has been used clinically in the treatment of alcoholism. It has also been associated with abuse and is a controlled substance. Although GABAergic mechanisms may be involved, the manner in which sodium oxybate acts to reduce excessive sleepiness is unknown [18]. Hypocretin system The hypocretins (also known as orexins) are two, recently discovered, peptide neurotransmitters localized in a hypothalamic neural system with important functions in the control of wakefulness [19]. Neurons containing the hypocretins project to many brain areas and the released transmitters activate two receptors (Hcrtr1 and Hcrtr2). A role for this system in sleep and wakefulness as well as in narcolepsy was proposed when it was demonstrated that a strain of dogs with genetic narcolepsy showed a mutation in the gene which codes for the Hcrtr2 receptor. Additionally, it has been found that genetically modified mice in which hypocretins or hypocretin receptors have been deleted (“knock-out” mice) show disturbed patterns of sleep and wakefulness which resemble human narcolepsy. Although most cases of human narcolepsy
New perspectives for the treatment of disorders of sleep and arousal do not seem to have a genetic basis it seems that disorders of the hypocretin system, possibly due to autoimmune processes, may play an important role [20]. The discovery of such a clearly localized hypocretin system has generated hope that drugs which target these transmitters and their receptors may be particularly useful in treating sleep disorders and perhaps other diseases of the CNS. Many research programmes are underway although, as yet, no molecules seemed to have reached the stage of clinical testing.
Circadian rhythms and melatonin
Ramelteon O
N H O
Agomelatine O
Sleep is considered to be controlled by both homeostatic and circadian factors and some sleep disorders may be related to disturbances of circadian control. Physiological processes which show clear circadian rhythms, including sleep, are under the control of the suprachiasmatic nuclei, found in the anterior hypothalamus, which is considered to be the brain’s major circadian pacemaker or clock [21]. There has long been interest in the modifying the actions of the pacemaker by modulating its neurophysiological functions or even manipulating the activity of the genes which show circadian patterns of expression (“clock genes”) [22]. One mechanism by which the suprachiasmatic nuclei exert control of physiological systems is through the synthesis and release of the hormone melatonin from the pineal gland. Many claims have been made for the health-improving actions of melatonin supplements although it has never been recognized as a medication. However, there is evidence that melatonin can exert mild sedative effects in patients with insomnia and can be helpful in aiding the resetting of the circadian clock under circumstances such as travel across several time zones (jet lag) [23]. Melatonin exerts its chronobiotic action by activating two receptors (MT1 and MT2) and a number of molecules, generally chemical derivatives of melatonin, with MT1 and or MT2 activating actions have been described (figure 2 shows two examples). Such compounds may have potential in treating diseases where circadian processes play an
N H O
Figure 2. Chemical structures of ramelteon and agomelatine; both are agonists at melatonin receptors. Ramelteon is used in the USA in the treatment of insomnia characterized by problems of sleep onset. Agomelatine is being tested for its potential in the treatment of depression. Structures chimiques de ramelteon et agomelatine ; deux agonistes des récepteurs de la melatonine. Ramelteon est prescrit aux ÉtatsUnis dans le traitement des troubles de l’endormissement. Agomelatine est actuellement évalué dans le traitement de la dépression.
important role including sleep disorders. The first melatonin agonist to become available is ramelteon which is used in patients with insomnia characterized by problems of sleep onset [24]. While this cannot be considered a chronobiotic action, ramelteon is also being investigated for its potential in several other sleep disorders including sleep disturbance induced by jet lag. Other melatonin agonists, including VEC-162 and LY-156735, may also have potential in similar conditions. Another melatonin receptor agonists, agomelatine, has been reported to show clinical antidepressant properties and to be particularly useful in patients suffering from depression with associated disturbances in their sleep-wake cycles [25].
273
D.J. Sanger et Coll.
Conclusions
10. Roth T, Soubrane C, Titeux L, Walsh JK, Zoladult Study Group. Efficacy and safety of zolpidem-MR: a double-
Basic and clinical research on sleep and sleep disorders has made considerable progress in recent years. In the clinic a better definition of different problems of sleep and arousal has been achieved and this is likely to lead to more effective methods of treatment. Laboratory studies continue to define the complex neural systems which underlie sleep and wakefulness and this, in turn should provide novel mechanisms on which to base drug discovery and development programmes. There is increasing interest in developing effective and safe drugs for patients with sleep disorders and, as outlined in this paper, many of the molecules currently emerging from this research have novel mechanisms of action and original pharmacological profiles. It is to be hoped that these efforts will insure that the next few years see a number of significant therapeutic advances.
blind, placebo-controlled study in adults with primary insomnia. Sleep Med 2006; 7: 397-406. 11. Landolt HP, Meier V, Burgess HJ, Finelli LA, Cattelin F, Achermann P et al. Serotonin-2 receptors and human sleep: effect of a selective antagonist on EEG power spectra. Neuropsychopharmacology 1999; 21: 455-66. 12. Bazil CW. Effects of antiepileptic drugs on sleep structure: are all drugs equal? CNS Drugs 2003; 17: 719-28. 13. Yanai K, Tashiro M. The physiological and pathophysiological roles of neuronal histamine: an insight from human positron emission tomography studies. Pharmacol Ther 2007; 113: 1-15. 14. Navab P, Guilleminault C. Emerging pharmacotherapeutic agents for insomnia: a hypnotic panacea? Expert Opin Pharmacother 2006; 7: 1731-8. 15. Keating GM, Raffin MJ. Modafinil: a review of its use in excessive sleepiness associated with obstructive sleep apnoea/hypopnoea syndrome and shift work sleep disorder. CNS Drugs 2005; 19: 785-803. 16. Ballon JS, Feifel D. A systematic review of modafinil:
References
Potential clinical uses and mechanisms of action. J Clin Psychiatry 2006; 67: 554-66. 17. Scharf MB. Sodium oxybate for narcolepsy. Expert Rev
1. Terzano MG, Rossi M, Palomba V, Smerieri A, Parrino L. New drugs for insomnia: comparative tolerability of zopiclone, zolpidem and zaleplon. Drug Saf 2003; 26(4): 26182. 2. Doble A. New insights into the mechanism of action of hypnotics. J Psychopharmacol 1999; 13(Suppl. 1): S11-20. 3. Sanger DJ, Depoortere H. The pharmacology and mechanism of action of zolpidem. CNS Drug Reviews 1998: 4: 323-40. 4. Bateson AN. Further potential of the GABA receptor in the treatment of insomnia. Sleep Med 2006; 7(Suppl. 1): S3-9. 5. Ebert B, Wafford KA, Deacon S. Treating insomnia: Current and investigational pharmacological approaches. Pharmacol Ther 2006; 112: 612-29. 6. Farrant M, Nusser Z. Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci 2005; 6: 215-29. 7. Neubauer DN. Indiplon: the development of a new hypnotic. Expert Opin Investig Drugs 2005; 14: 1269-76. 8. Atack JR. The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics. Expert Opin Investig Drugs 2005; 14: 601-18. 9. Moen MD, Plosker GL. Zolpidem extended-release. CNS Drugs 2006; 20: 419-26.
274
Neurother 2006; 6: 1139-46. 18. Pardi D, Black J. Gamma-hydroxybutyrate/sodium oxybate: neurobiology, and impact on sleep and wakefulness. CNS Drugs 2006; 20: 993-1018. 19. Nishino S, Kanbayashi T. Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Med Rev 2005; 9: 269-310. 20. Baumann CR, Bassetti CL. Hypocretins (orexins) and sleepwake disorders. Lancet Neurol 2005; 4(10): 673-82. 21. Zee PC, Manthena P. The brain’s master circadian clock: Implications and opportunities for therapy of sleep disorders. Sleep Med Rev 2007; 11: 59-70. 22. Touitou Y, Bogdan A. Promoting adjustment of the sleepwake cycle by chronobiotics. Physiol Behav 2006; 90: 294300. 23. Pandi-Perumal SR, Srinivasan V, Maestroni GJ, Cardinali DP, Poeggeler B, Hardeland R. Melatonin: Nature’s most versatile biological signal? FEBS J 2006; 273: 2813-38. 24. McGechan A, Wellington K. Ramelteon. CNS Drugs 2005; 19: 1057-65. 25. Zupancic M, Guilleminault C. Agomelatine: a preliminary review of a new antidepressant. CNS Drugs 2006; 20: 981-92.
Ann Pharm Fr 2007, 65 : 268-274
Médicaments du sommeil et de la vigilance New perspectives for the treatment of disorders of sleep and arousal D.J. Sanger, C. Soubrane, B. Scatton, Summary. A variety of molecules with novel mechanisms of
Résumé. Différents types de molécules ayant un nouveau
action are currently being evaluated for their potential as treat-
mécanisme d’action sont actuellement evalués dans le traite-
ments for sleep disorders. The GABA-A receptor complex
ment des troubles du sommeil. Bien que le complexe GABA-
remains an important target for hypnotic drugs (eg gaboxadol,
A demeure une cible essentielle pour les agents hypnotiques
indiplon). However, drugs acting through histamine, calcium
(gaboxadol, indiplon), d’autres mécanismes d’action impliquant
channels and serotonin receptors may also be of interest for
les récepteurs histaminiques ou sérotoninergiques ou encore
the treatment of insomnia. In the case of the 5HT2A subtype
les canaux calciques pourraient également être une voie inté-
of serotonin receptors, several molecules which improve sleep
ressante dans le traitement de l’insomnie. Plusieurs molécules
maintenance and modify sleep architecture by increasing slow
qui bloquent les récepteurs sérotoninergiques de type 5HT2A
wave sleep are currently being tested (eg eplivanserin). Two
et qui maintiennent le sommeil et modifient son architecture
new drugs with efficacy in excessive sleepiness (modafinil,
en augmentant sa composante lente sont actuellement en
sodium oxybate) have improved the treatment of this condition.
développement clinique (ex, eplivanserin). Dans le cas de la
However, the mechanisms of action of these agents are poorly
somnolence diurne excessive, deux nouveaux produits (moda-
understood. The recent discovery of the hypocretin arousal sys-
finil et oxybate de sodium) sont récemment venus améliorer
tem in the hypothalamus may aid the identification of additional new drugs. An agonist at receptors for the pineal hormone melatonin is available in some countries (ramelteon) but is currently used only for the treatment of insomnia associated with difficulties of sleep onset. Additional melatonin receptor agonists are being developed and may have potential for treating several conditions including circadian rhythm disorders and depression.
les possibilités thérapeutiques. Leur mécanisme d’action demeure toutefois inexpliqué. La découverte récente du système excitateur hypocrétine au niveau de l’hypothalamus pourrait faciliter l’identification de nouvelles molécules. Un agoniste des récepteurs de la mélatonine (ramelteon) est commercialisé dans certains pays pour le traitement des troubles de l’endormissement seulement. D’autres agonistes des récepteurs de la mélatonine en cours de développement pourraient avoir un potentiel thérapeutique dans plusieurs indications, dont les troubles des rythmes circadiens et la dépression. Mots-clés : Insomnie, Vigilance, Sérotonine, GABA, Mélatonine.
Key-words: Insomnia, Arousal, GABA, Serotonin, Melatonin.
Nouvelles perspectives dans le traitement des troubles du sommeil et de la vigilance. D.J. Sanger, C. Soubrane, B. Scatton. Ann Pharm Fr 2007 ; 65 : 268-274.
Sanofi-Aventis Recherche, 31, avenue Paul Vaillant-Couturier, F 92220 Bagneux. Présentation devant les Académies nationales de pharmacie et de médecine, lors d’une séance commune, le 29 novembre 2006, à l’École du Val-de-Grâce, Paris. Correspondance : D.J. Sanger, à l’adresse ci-dessus. E-mail : [email protected]
268
New perspectives for the treatment of disorders of sleep and arousal
Insomnia Insomnia, consisting of problems in initiating sleep, maintaining sleep and non-restorative sleep, is common, and, in some patients may be chronic and disabling. Although sleep hygiene advice may be very useful and psychological techniques such as cognitive behavioural therapy have been found helpful in alleviating this condition, drug therapy remains the most convenient treatment. The older, barbiturate “sleeping pills” were largely replaced as the treatment of choice by the much safer benzodiazepines such as temazepam and triazolam some years ago. However, benzodiazepines themselves have been considered to have a number of undesirable effects and the more recently introduced molecules zolpidem, zopiclone and zaleplon are more appropriate for many patients [1]. Benzodiazepines exert their pharmacological effects by binding to a specific binding site (the BZ receptor) which forms part of the macromolecular receptor complex known as the GABA-A subtype of receptors for the brain’s major inhibitory neurotransmitter gamma-hydroxy-butyric acid (GABA). Molecules such as the benzodiazepines which act as agonists at BZ sites potentiate the effects of the transmitter and in this way exert their sedative/hypnotic and other pharmacological actions. Zolpidem, zopiclone and zaleplon also act at BZ sites associated with GABA-A receptors. However, zolpidem and zaleplon have selectivity for a certain sub-population of these receptors containing alpha1 subunits and zopiclone, while not showing receptor subtype selectivity, may bind to BZ receptors in a manner different from that shown by benzodiazepines. These differences probably explain the pharmacological and clinical differences from traditional benzodiazepines [2, 3]. GABA-A receptors as a target for development of new drugs Most past and present hypnotic drugs exert their therapeutic actions through GABA-A receptors (at least some of the effects of barbiturates and ethanol are also produced by enhancing GABAergic activity), and these receptors remain an important target for new hypnotic drug discovery and deve-
Table I. — New Hypnotic Drugs Acting at the GABA-A Receptor Complex Currently in Clinical Development Nouveaux agents hypnotiques agissant sur le complexe GABA-A actuellement en développement clinique. Drug
Mechanism
Gaboxadol
Active at receptors with alpha4 and delta subunits. Selective for extrasynaptic receptors
Indiplon
BZ receptor agonist with selectivity for receptors with alpha1 subunits
NG2-73
BZ receptor partial agonist
EVT-201
BZ receptor partial agonist
lopment [4]. Table I lists four novel molecules currently being tested as potential hypnotics. Gaboxadol and indiplon are in late stage and NG273 and EVT-201 in earlier stage clinical trials. Gaboxadol is a relatively old compound, previously know as THIP, which reached clinical testing for several disorders including pain and epilepsy. However, although never brought to the market, it was found to have sedative properties, thought undesirable at the time. When it was also shown to produce effects on sleep architecture quite different from those of older hypnotics, the idea of testing gaboxadol as a potential treatment for insomnia was born. Benzodiazepines are clearly effective in inducing and maintaining sleep but tend to produce light sleep and even decrease the proportion of deep, slow wave sleep. In contrast, gaboxadol produces a substantial increase in slow wave sleep in both experimental animals and humans. It is not known whether this, in itself, can lead to clinical benefits in patients suffering from insomnia. However, clinical trials are currently underway and should help to define whether the molecule could have advantages over the currently available drugs [5]. The manner in which gaboxadol modulates GABA-A receptor function also differs from those of benzodiazepines and other hypnotics. Gaboxadol does not bind to the BZ site but has been shown to have selectivity for GABA-A receptors containing delta subunits. These receptors seem to be particularly dense in the thalamus, a brain region often associated with the control of sleep, and are found on neural membranes situated outside synaptic areas. The biology of these extra-synaptic
269
D.J. Sanger et Coll. receptors has been subject to considerable research in recent years and it seems that they modulate synaptic transmission and neuronal excitability in a way different from receptors found within the synapses [6]. It is possible, therefore, that gaboxadol will show clinical differences from older drugs in patients with insomnia1. Indiplon is a derivative of zaleplon and has a similar pharmacological profile including selectivity for GABA-A receptors containing alpha1 subunits [7]. Like gaboxadol, it is currently being tested in a range of clinical trials in insomniac patients but only brief descriptions of the results have thus far been published. A novel aspect of indiplon’s development is that two pharmaceutical forms are being tested having immediate release and modified release characteristics. It is hoped that this will allow for treatment of a wider range of patients with forms of insomnia (see below). NG2-73 and EVT-201 both bind to BZ sites and have the unusual characteristic of being partial agonists. This indicates that, even when they occupy a large proportion of available receptors they do not stimulate the same degree of receptor output as full agonists. In pharmacological tests in vitro and in vivo procedures in experimental animals, compounds characterized as partial agonists produce anticonvulsant and anxiolytic-like effects without sedation. Several such molecules reached the clinic in the hope that they would be effective treatments for anxiety but, unlike most other anxiolytics, would not produce the side effect of sedation. Unfortunately, all such development programmes have failed and it has been found that BZ receptor partial agonist do indeed produce sedation in humans [8]. It will therefore be particularly interesting to see whether NG273 and EVT-201 are shown to be useful treatments for insomnia and, particularly, whether they have any advantages over the BZ receptor full agonists already available. New Pharmaceutical Forms. It has become increasing clear that not all forms of insomnia are the same and that different patients may best benefit from drugs with different pharmacological or pharmacokinetic characteristics. Some years 1
Note added in proof: the development programme for gaboxadol has recently been discontinued.
270
ago it was realized that many older hypnotic drugs had elimination half-lives and durations of actions which were too long, leading to impaired performance in the morning. This led to the development of drugs such as zolpidem which has a rapid onset and short duration of action (elimination half-life of approximately 2.5 hours). However, in some patients with particular problems of sleep maintenance with frequent waking in the middle or later sections of the night, zolpidem was deemed to be too short acting. A modifed release form of the drug was therefore developed and is now available in several countries [9]. Zolpidem-MR consists of a tablet with a biphasic pattern of release of the active drug. It has been shown to be particularly effective in reducing time awake during the middle of the night in patients with chronic insomnia [10]. As noted above, a potentially similar modified release form of indiplon is also being tested and plans have been reported for the development of a modified release form of zaleplon. Several other pharmaceutical forms of zolpidem, mostly aiming at more rapid release and buccal absorption have also been described but only preliminary data seem so far to be available. Serotoninergic drugs It has been known for many years that neural pathways utilizing serotonin as their primary neurotransmitter play important roles in the control of sleep states. However, drugs which modulate serotoninergic transmission by, for example, stimulating or blocking receptors for this transmitter, have never found clinical use in the treatment of insomnia. This may soon change as several agents with selective activity as antagonists or inverse agonists at the 5HT2A subtype of serotonin receptors are currently being tested in patients with sleep disorders (fig. 1). 5HT2A antagonists do not show pharmacological effects similar to traditional sedative/hypnotic agents — they do no reduce the latency to fall asleep, for example. However, they do modify sleep architecture by selectively increasing slow wave sleep [11]. Table II shows some data from a study in which the 5HT2A antagonist eplivanserin was found to induce a major increase in slow wave sleep in healthy volunteers without affecting other sleep parameters. Preliminary evidence from studies of patients with insomnia have shown that eplivanserin as well as other
New perspectives for the treatment of disorders of sleep and arousal Table II. — Effects of Eplivanserin on Sleep Parameters in Healthy Subjects. Effets de l’Eplivanserin sur les paramètres du sommeil des volontaires sains.
Pruvanserin O
HN
N
Placebo
Eplivanserin 1 mg
Sleep Latency
11,8
15,8
TST
441
450
REM
97,7
85,6
SWS
8 202
143,8*
All values are in minutes. TST: total sleep time, REM: rapid eye movement (paradoxical) sleep, SWS: slow wave sleep (stages 3 and 4). * p<0.001 difference from placebo. Data are taken from Landolt et al (2006) and show sleep parameters recorded in 10 subjects over a 10 hour overnight period. Toutes les valeurs sont exprimées en minutes. TST : total sleep time, REM : rapid eye movement (sommeil paradoxal), SWS : slow wave sleep (stades 3 et 4). Différence versus placebo * p < 0,001. Données de Landolt et al (2006) montrant les valeurs des parameters du sommeil enregistrés sur dix heures au cours de la nuit chez dix sujets.
N
N
F
Eplivanserin
F O N
N
HO
molecules with a similar mechanism of action can also increase deep sleep in this population and, in addition, can improve sleep maintenance and sleep quality. If clinical testing continues to be successful, such molecules may eventually become available for patients with disturbed sleep but who do not suffer from difficulties of sleep initiation.
Volinanserin OH
O O
N
Other mechanisms Another group of molecules which have been reported to modify sleep architecture without decreasing sleep onset latency are derivatives of the antiepileptic drugs gabapentin and pregabalin. These molecules appear to act selectivity on the alpha2-delta calcium channel and may have potential in treating sleep disorders [12]. Molecules with antihistaminergic effects are well known to produce sedation and some have been used as sleep aids [12]. This is despite the fact that modern, well-controlled clinical trials have never been described. However, histamine is a neurotransmitter involved in the control of sleep and wakefulness, and it is considered that novel compounds with selective antagonist activity at the H1 receptor subtype may have potential in treating insomnia. The old antidepressant agent doxepin acts at several transmitter systems
F
Figure 1. Chemical structures of three selective 5HT2A antagonists currently being tested in the clinic for their potential in the treatment of insomnia. Pruvanserin was previously known as EMD-281044, eplivanserin as SR-46349 and volinanserin as M100907 Structures chimiques de trois agonistes 5HT2 actuellement testés en clinique pour leur potentiel thérapeutique dans l’insomnie. Pruvanserin, eplivanserin et volinanserin étaient préalablement connus respectivement sous les codes EMD-281044, SR-46349 et M100907.
but has particularly high affinity for H1 receptors. It has been suggested, therefore, that doses of this drug considerably lower than those used to treat depression may be considered selective H1 antagonists. Such doses are currently being tested in patients with insomnia [14]. Preliminary descriptions of the results of these trials suggest
271
D.J. Sanger et Coll. good efficacy, particularly on measures of sleep maintenance. Another selective H1 antagonist, HY- 12075 is also in early clinical testing.
Problems of decreased arousal Although the number of patients suffering from hypersomnias and requiring treatment to increase arousal is certainly smaller than those with insomnia, they nevertheless represent a significant population. The relatively rare condition of narcolepsy, for example, is characterized by cataplexy and daytime sleepiness and, until recently, was treated with psychomotor stimulant drugs such as amphetamines. There are also large numbers of patients who have problems of daytime sleepiness produced by medical conditions such as obstructive sleep apnea or fibromyalgia, or disrupted rhythms of life which lead to disturbed sleep, including night work and international travel. Treatment of problems of excessive sleepiness will probably be considerably improved by several recent advances in basic research and drug development. Modafinil This drug is a novel molecule with wake-promoting effects [15]. It does not produce the same psychomotor stimulation and euphoria as drugs such as the amphetamines and is therefore considered to have little potential to lead to abuse or dependence. Currently, modafinil is used to treat daytime sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnoea and shift work. It has been shown to have clear but modest efficacy in these conditions and is generally well tolerated. Modafinil provides an undoubted step forward in the treatment of excessive sleepiness and might be expected to point the way for new drug discovery programmes aimed an identifying yet more efficacious drugs. Unfortunately, however, despite considerable research, the mechanism of action of the drug is still very poorly understood. It seems that modafinil may act primarily at hypothalamic pathways involved in the control of wakefulness but the exact neurotransmitter or other neuropharmacological mechanism involved has yet to be identified. Roles for dopamine, noradrenaline, GABA, glutamate and orexin, among other neu-
272
rotransmitters, have been proposed but it remains to be determined which, if any of these systems plays the main part in modafinil’s clinical actions [16]. Sodium oxybate Another agent with clinical efficacy in the treatment of excessive sleepiness but whose mechanism of action is not well understood, is sodium oxybate [17]. Sodium oxybate is the sodium salt of gamma-hydroxybutyrate (GHB) and is used for the treatment of patients with narcolepsy and improves both daytime sleepiness and cataplexy. Clinical studies also indicate that it may have potential for the treatment of excessive sleepiness associated with other conditions such as fibromyalgia. GHB is an endogenous substance, found in the brain, and is a metabolite of GABA. It was first synthetised in the 1960’s by H Laborit and the pharmacological properties of endogenous administered GHB have been extensively investigated. In addition to sleep promoting actions a variety of other effects including anaesthesia and analgesia have been described and GHB has been used clinically in the treatment of alcoholism. It has also been associated with abuse and is a controlled substance. Although GABAergic mechanisms may be involved, the manner in which sodium oxybate acts to reduce excessive sleepiness is unknown [18]. Hypocretin system The hypocretins (also known as orexins) are two, recently discovered, peptide neurotransmitters localized in a hypothalamic neural system with important functions in the control of wakefulness [19]. Neurons containing the hypocretins project to many brain areas and the released transmitters activate two receptors (Hcrtr1 and Hcrtr2). A role for this system in sleep and wakefulness as well as in narcolepsy was proposed when it was demonstrated that a strain of dogs with genetic narcolepsy showed a mutation in the gene which codes for the Hcrtr2 receptor. Additionally, it has been found that genetically modified mice in which hypocretins or hypocretin receptors have been deleted (“knock-out” mice) show disturbed patterns of sleep and wakefulness which resemble human narcolepsy. Although most cases of human narcolepsy
New perspectives for the treatment of disorders of sleep and arousal do not seem to have a genetic basis it seems that disorders of the hypocretin system, possibly due to autoimmune processes, may play an important role [20]. The discovery of such a clearly localized hypocretin system has generated hope that drugs which target these transmitters and their receptors may be particularly useful in treating sleep disorders and perhaps other diseases of the CNS. Many research programmes are underway although, as yet, no molecules seemed to have reached the stage of clinical testing.
Circadian rhythms and melatonin
Ramelteon O
N H O
Agomelatine O
Sleep is considered to be controlled by both homeostatic and circadian factors and some sleep disorders may be related to disturbances of circadian control. Physiological processes which show clear circadian rhythms, including sleep, are under the control of the suprachiasmatic nuclei, found in the anterior hypothalamus, which is considered to be the brain’s major circadian pacemaker or clock [21]. There has long been interest in the modifying the actions of the pacemaker by modulating its neurophysiological functions or even manipulating the activity of the genes which show circadian patterns of expression (“clock genes”) [22]. One mechanism by which the suprachiasmatic nuclei exert control of physiological systems is through the synthesis and release of the hormone melatonin from the pineal gland. Many claims have been made for the health-improving actions of melatonin supplements although it has never been recognized as a medication. However, there is evidence that melatonin can exert mild sedative effects in patients with insomnia and can be helpful in aiding the resetting of the circadian clock under circumstances such as travel across several time zones (jet lag) [23]. Melatonin exerts its chronobiotic action by activating two receptors (MT1 and MT2) and a number of molecules, generally chemical derivatives of melatonin, with MT1 and or MT2 activating actions have been described (figure 2 shows two examples). Such compounds may have potential in treating diseases where circadian processes play an
N H O
Figure 2. Chemical structures of ramelteon and agomelatine; both are agonists at melatonin receptors. Ramelteon is used in the USA in the treatment of insomnia characterized by problems of sleep onset. Agomelatine is being tested for its potential in the treatment of depression. Structures chimiques de ramelteon et agomelatine ; deux agonistes des récepteurs de la melatonine. Ramelteon est prescrit aux ÉtatsUnis dans le traitement des troubles de l’endormissement. Agomelatine est actuellement évalué dans le traitement de la dépression.
important role including sleep disorders. The first melatonin agonist to become available is ramelteon which is used in patients with insomnia characterized by problems of sleep onset [24]. While this cannot be considered a chronobiotic action, ramelteon is also being investigated for its potential in several other sleep disorders including sleep disturbance induced by jet lag. Other melatonin agonists, including VEC-162 and LY-156735, may also have potential in similar conditions. Another melatonin receptor agonists, agomelatine, has been reported to show clinical antidepressant properties and to be particularly useful in patients suffering from depression with associated disturbances in their sleep-wake cycles [25].
273
D.J. Sanger et Coll.
Conclusions
10. Roth T, Soubrane C, Titeux L, Walsh JK, Zoladult Study Group. Efficacy and safety of zolpidem-MR: a double-
Basic and clinical research on sleep and sleep disorders has made considerable progress in recent years. In the clinic a better definition of different problems of sleep and arousal has been achieved and this is likely to lead to more effective methods of treatment. Laboratory studies continue to define the complex neural systems which underlie sleep and wakefulness and this, in turn should provide novel mechanisms on which to base drug discovery and development programmes. There is increasing interest in developing effective and safe drugs for patients with sleep disorders and, as outlined in this paper, many of the molecules currently emerging from this research have novel mechanisms of action and original pharmacological profiles. It is to be hoped that these efforts will insure that the next few years see a number of significant therapeutic advances.
blind, placebo-controlled study in adults with primary insomnia. Sleep Med 2006; 7: 397-406. 11. Landolt HP, Meier V, Burgess HJ, Finelli LA, Cattelin F, Achermann P et al. Serotonin-2 receptors and human sleep: effect of a selective antagonist on EEG power spectra. Neuropsychopharmacology 1999; 21: 455-66. 12. Bazil CW. Effects of antiepileptic drugs on sleep structure: are all drugs equal? CNS Drugs 2003; 17: 719-28. 13. Yanai K, Tashiro M. The physiological and pathophysiological roles of neuronal histamine: an insight from human positron emission tomography studies. Pharmacol Ther 2007; 113: 1-15. 14. Navab P, Guilleminault C. Emerging pharmacotherapeutic agents for insomnia: a hypnotic panacea? Expert Opin Pharmacother 2006; 7: 1731-8. 15. Keating GM, Raffin MJ. Modafinil: a review of its use in excessive sleepiness associated with obstructive sleep apnoea/hypopnoea syndrome and shift work sleep disorder. CNS Drugs 2005; 19: 785-803. 16. Ballon JS, Feifel D. A systematic review of modafinil:
References
Potential clinical uses and mechanisms of action. J Clin Psychiatry 2006; 67: 554-66. 17. Scharf MB. Sodium oxybate for narcolepsy. Expert Rev
1. Terzano MG, Rossi M, Palomba V, Smerieri A, Parrino L. New drugs for insomnia: comparative tolerability of zopiclone, zolpidem and zaleplon. Drug Saf 2003; 26(4): 26182. 2. Doble A. New insights into the mechanism of action of hypnotics. J Psychopharmacol 1999; 13(Suppl. 1): S11-20. 3. Sanger DJ, Depoortere H. The pharmacology and mechanism of action of zolpidem. CNS Drug Reviews 1998: 4: 323-40. 4. Bateson AN. Further potential of the GABA receptor in the treatment of insomnia. Sleep Med 2006; 7(Suppl. 1): S3-9. 5. Ebert B, Wafford KA, Deacon S. Treating insomnia: Current and investigational pharmacological approaches. Pharmacol Ther 2006; 112: 612-29. 6. Farrant M, Nusser Z. Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci 2005; 6: 215-29. 7. Neubauer DN. Indiplon: the development of a new hypnotic. Expert Opin Investig Drugs 2005; 14: 1269-76. 8. Atack JR. The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics. Expert Opin Investig Drugs 2005; 14: 601-18. 9. Moen MD, Plosker GL. Zolpidem extended-release. CNS Drugs 2006; 20: 419-26.
274
Neurother 2006; 6: 1139-46. 18. Pardi D, Black J. Gamma-hydroxybutyrate/sodium oxybate: neurobiology, and impact on sleep and wakefulness. CNS Drugs 2006; 20: 993-1018. 19. Nishino S, Kanbayashi T. Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Med Rev 2005; 9: 269-310. 20. Baumann CR, Bassetti CL. Hypocretins (orexins) and sleepwake disorders. Lancet Neurol 2005; 4(10): 673-82. 21. Zee PC, Manthena P. The brain’s master circadian clock: Implications and opportunities for therapy of sleep disorders. Sleep Med Rev 2007; 11: 59-70. 22. Touitou Y, Bogdan A. Promoting adjustment of the sleepwake cycle by chronobiotics. Physiol Behav 2006; 90: 294300. 23. Pandi-Perumal SR, Srinivasan V, Maestroni GJ, Cardinali DP, Poeggeler B, Hardeland R. Melatonin: Nature’s most versatile biological signal? FEBS J 2006; 273: 2813-38. 24. McGechan A, Wellington K. Ramelteon. CNS Drugs 2005; 19: 1057-65. 25. Zupancic M, Guilleminault C. Agomelatine: a preliminary review of a new antidepressant. CNS Drugs 2006; 20: 981-92.