New treatment options for sleep disorders
Novel selective melatonin MT2 receptor agonist in the treatment of insomnia
Gabriella Gobbi, Canada
Orexin receptor antagonists and insomnia treatment: state of the art
Anthony Gotter, US
Development of piromelatine, a novel multimodal sleep medicine
Nava Zisapel, Israel
The brain H3-receptor as a novel therapeutic target for vigilance and sleep-wake disorders Abstract
Jian Sheng Lin , France
Chairs: Gabriella Gobbi and Anton Y. Bespalov
Prevalence insomnia in Canada and Europe
0
10
20
30
40
50
Insomnia symptoms Insomnia disorder
40.4%
13.4%
Resp
ondents
(%
)
0
10
20
30
40
50
Insomnia symptoms Insomnia disorder
34.5%
9.8%Resp
ondents
(%
)
1. Morin et al. Can J Psychiatry. 2011;56:540-548; 2. Ohayon et al. Sleep Med. 2009;10:952-960.
Canadian survey1
on sleep and related factors
(N=2000)
European survey2
on insomnia and sleep symptoms
(N=25,579)
Prevalence in the American Insomnia Survey
10,094 members of a managed health care plan
Prevalence 23.6%*
Insomnia symptoms: about 45%
Risk of insomnia higher in: Women vs men
Older age vs younger groups (18-64 vs >65 y)
Disabled or retired vs employed
Shift workers vs day workers
Obese vs normal BMI
Diagnosis based on any one of 3 systems: DSM-IV-TR, ICD-10, RDC/ICSD-2.*Insomnia assessed using Brief Insomnia Questionnaire (BIQ).
Roth et al. Biol Psychiatry. 2011;69:592-600.
Insomnia and Societal Burden
Psychiatric•Increased risks of depression and alcohol dependence1,2
Health•Increased risks of hypertension, metabolic syndrome, and coronary heart disease2
Occupational•Decreased productivity and increased absenteeism1,2
Economic •Increased health care costs1,2
Public safety •Increased risks of accidents1
1. Léger, Bayon. Sleep Med Rev. 2010;14:379-389;
2. Buysse. JAMA. 2013;309:706-716.
DRUG DISCOVERY FOR SLEEP DISORDERS
600 BC: Alcohol as therapeutics
1869
Chloral Hydrate
1903
Barbiturates
1960
Benzodiazepines (chlordiazepoxide)
1986
Benzodiazepine-derivates(zopiclone)
2005
MLT agonist Ramelteon (US)
Circadin (EU)
2014
Orexin antagonists
Important need of novel targets and novel drug discovery
Novel selective melatonin
MT2 partial agonists for
the treatment of insomnia
Gabriella Gobbi, MD, PhD
Neurobiological Psychiatry Unit
Department of Psychiatry, McGill University
Montréal, Canada
Sleep Stages: EEG Features1,2
• High muscle tone
EEG activity:
• Low voltage fast activity in the beta range (15–30 Hz)
Wakefulness
• Transitional stage
• Similar to drowsy waking
EEG activity:
• Frequency begins to slow
• Alpha (8–14 Hz) activity mostly at posterior sites
Light sleepstage 1
• Light sleep
• Low muscle tone, slow rolling eye movements
EEG activity:
• Sleep spindles(7–14 Hz) andK-complexes
• Frequency slows to the theta range (4–8 Hz)
Light sleepstage 2
• Slow-wave sleep (SWS)
EEG activity:
• Strong delta (0.5–4 Hz) activity
• Large amplitude increases
Deep SWSstage 3 & 4
• Rapid eye movement (REM)
• Muscle atonia
• Active dreams
• Rate & variability of autonomic nervous system function
EEG activity:
• Returns to profile similar to wakefulness (low voltage fast activity)
REM
1. Iber et al. AASM manual for the scoring of sleep and associated events. http://www.aasmnet.org/scoringmanual/default.aspx;
2. Brown et al. Physiol Rev. 2012;92:1087-1187.
NREM REM
1. Gander. Sleep in the 24-Hour Society. Lower Hutt, NZ: The Open Polytechnic of New Zealand, 2003;
2. Colten, Altevogt, eds. Sleep Disorders and Sleep Deprivation. 2006; www.nap.edu.
Visualizing Sleep Quantity and Quality
Hypnograms showing distribution of normal sleep
pattern1
Over the course of normal sleep, SWS and REM sleep alternate cyclically2
Schematic representation Normal subject
Melatonin & sleep: Clinical
Melatonin (N-acetyl-5-methoxytryptamine, MLT),synthesized by the pineal gland, has beenreported to have hypnotic effects in humans,although results are still controversial (Brzezinskiet al., 2005; Buscemi et al., 2006).
Controversial studies on the role of melatonin insleep, even if there is a concordance on thesoporific effect and sleep-inducing effects ofmelatonin.
Melatonin & sleep: Animal
Animal studies have demonstrated that MLTreduces time to sleep onset and increases bothNREMS and REMS (Holmes and Sugden, 1982;Mirmiran and Pevet, 1986), both effects beingblocked by the GABAA receptor antagonistsflumazenil and picrotoxin (Wang et al., 2003a).
Other studies showed little or no effect (Maillietet al., 2001; Wang et al., 2003).
MT1 receptor
MT2 receptor
Melatonin and its receptors
c-AMP
PIP-2
c-AMP
PIP-2
Guanylyl
cyclase
MLT1a
MLT1b
Dubocovich et al., Pharm Reviews , 2010
MT1 and MT2 in sleep
Which receptor is involved in sleep?
Lack of sleep studies using selective MT1 or MT2
ligands
Lack of sleep studies in MT1KO and MT2KO.
Ligand-model provides 3D-QSAR and SAR analysisbased on 100s of compounds
Agonist
pharmacophore
3D-QSAR
model
Spadoni G.et al. J. Med. Chem. 1997, 40, 1990
Mor M. et al. J. Med. Chem. 1998, 41, 3831
Rivara S. et al., J. Med. Chem. 2005, 48, 4049Purple: rhodopsin
Green: MT2
Orange MT2 TM5
UCM765 and UCM924: novel MT2 selective partial agonists
Rivara et al., JMC, 2007
UCM 765
N-{2-[(3-methoxyphenyl)phenylamino]ethyl}acetamide
UCM 924
N-{2-[(3-bromophenyl)-(4-fluorophenyl)amino]ethyl}acetamide
Rivara et al., CMC, 2009
Pro-Lead Compound Lead Compound
N-(Substituted-anilino-ethyl)amides
UCM765 and UCM924: novel MT2 selective partial agonists
UCM-765 UCM-924
MT1 (pKi) 8.38
Partial agonist
6.75
Antagonist
MT2 (pKi)10.18
Partial agonist
10.2
Partial agonist
F% (p.o) 0.9
6.3 (23.7%
oral
formulation)
T1/2 (min)44 IV 39 IV
68 PO
Rivara et al., 2007, 2009
LEADPRO-LEAD
Effects of UCM765 on sleep parameters
Ochoa-Sanchez et al., J.Neuroscience, 2011
0
50
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450
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Veh 20 40 60
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0100
Veh 20 40 60
Veh 20 40 60
NREM
REM Wakefulness
UCM765 (mg/kg, s.c.)
UCM765 (mg/kg, s.c.) UCM765 (mg/kg, s.c.)
**
**
*
8090
100
* *
Veh 20 40 60
UCM765 (mg/kg, s.c.)
NREM
0
5
10
15
20
25
30
* *
Total time Total time
Total timeLatency
Light phase
Dark phase
Light phase
Dark phase
Light phase
Dark phase
+48%
-59%
MELATONIN (40 mg/kg)
VEH
UCM924 (40 mg/kg)
UCM793 (40 mg/kg)
UCM924, MLT and UCM793 (40 mg/kg) on NREM sleep 24 hours analysis
Ochoa-Sanchez et al, Neuroscience Letters 201421
MLT, UCM793, UCM924, 24 hours analysis (total Time)
Latency to sleep
NREM REM Wakefullness
MLT δ
Non-selective MT1-MT2
MT2 selective
δ
Ochoa-Sanchez et al, Neuroscience Letters 2014
If MT2 receptors are located in the Rt nuclei,
the UCM765 should be able to activate these neurons
Hypothesis
MT2 ANTAGONIST 4P-PDOT
The effect of the partial agonist is blocked by the antagonist
H3CH2COCHN
MT2 receptors (pKi = 8.8)
MT1 receptors (pKi = 6.3)
(Dubocovic et al., 1997)
The pharmacological activation of MT2 receptors promotessleep, in particular NREM or SWS and decrease the latencyto sleep
Melatonin decreases the latency to sleep but not sleepduration
The MT2 receptors are localized in the reticular thalamus,and they promote NREM through the rhythmic and burstactivation of reticular thalamic neurons, which is thehallmark of NREM/SWS.
The MT2 receptor represents a novel target for hypnotics
Conclusion 1
24 h sleep-wake analysis
Comai et al., Behavior Brain Res, 2013
Sleep recording in MT1, MT2 and MT1-MT2knockout mice
Tim
e(m
in)
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450
Light Dark
Total time
Tim
e(m
in)
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50
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250
300
350
400
450
WT -/-MT1-/-MT2
-/-MT1-/-MT2 WT -/-MT1
-/-MT2-/-MT1
-/-MT2
Light Dark
WT -/-MT1-/-MT2
-/-MT1-/-MT2 WT -/-MT1
-/-MT2-/-MT1
-/-MT2
Total time
NREM sleep
4 second period analysis
Comai et al., Behavior Brain Res, 2013
10 second period analysis
NREM decreased in MT2 KO , but increased in MT1 KO
NREM sleep in MT1, MT2 and MT1-MT2knockout mice:
NREM decreases in MT2 KO (light)
Comai et al., Behavior Brain Res, 2013
Light DarkT
ime
(min
)
Total time
0
20
40
60
80
100
120
WT -/-MT1-/-MT2
-/-MT1-/-MT2 WT -/-MT1
-/-MT2-/-MT1
-/-MT2
Tim
e(m
in)
0
20
40
60
80
100
120
Light DarkWT -/-MT1
-/-MT2-/-MT1
-/-MT2 WT -/-MT1-/-MT2
-/-MT1-/-MT2
Total time
REM sleep
no light/dark difference
no light/dark difference
Comai et al., Behavior Brain Res, 2013
4 second period analysis 10 second period analysis
REM decreases only in MT1 KO
Blunted light-dark difference in MT1 KO
REM sleep in MT1, MT2 and MT1-MT2 knockout mice:
REM decreases only in MT1 KO
Comai et al., Behavior Brain Res, 2013
NREM REM WAKEFULNESS
MT1 knockout *
MT2 knockout
MT1-MT2
knockout
(24)
Differential role of receptors
Comai et al., 2013* 10 sec analysis
Conclusion 2
The MT1 and MT2 receptor have a differential role in sleepregulation, this role could explain the relative low effect ofnon-selective MT1-MT2 agonist, including melatonin, andthe lack of significant sleep impairment in double MT1-MT2 knockout
Genetic and pharmacological manipulation of MT2 receptorhas confirmed the selective implication of this receptor inNREM
Gabriella Gobbi’s lab
EEG/EMG & Electrophysiology, Behaviour, Pain
• Dr Rafael Ochoa Sanchez
• Dr Stefano Comai
• Dr Sergio Dominguez-Lopez
• Dr Francis Rodriguez Bambico
• Dr Quentin Rainer
• Marta Lopez-Canul
Immunohistochemistry
• Dr Baptiste Lacoste
AcknowledgmentsPharmacology and antibodies, Immunohisto
• Franco Fraschini (Univ. of Milan, Italy)
• Deborah Angeloni (Scuola Superiore Sant’Anna, Pisa, Italy)
• Laurent Descarries (Univ. of Montreal, Canada)
Modeling and Synthesis UCM 765
• Giorgio Tarzia (Univ. of Urbino, Italy)
• Gilberto Spadoni (Univ. of Urbino, Italy)
• Annalida Bedini (Univ. of Urbino, Italy)
• Marco Mor (Univ. of Parma, Italy)
• Silvia Rivara (Univ. of Parma, Italy)
Knockout-mice
• David Weaver (Univ. of Massachusset, US)
• Steven Reppert (Univ. of Massachusset, US)
Pain models
• Sabatino Maione (Second Univ. of Naples, Italy)
• Enza Palazzo (Second University of Naples, Italy)
• Vinicio Granados Soto (CINVESTAV, Mexico City, Mexico)
Grants support: CIHR, FRSQ, CFI, MSBiV, MDEIE