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Unveiling the role of melatonin MT 2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology

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Review Paper CCNP Award Paper Unveiling the role of melatonin MT 2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology Stefano Comai, PhD; Gabriella Gobbi,
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Review Paper CCNP Award Paper Unveiling the role of melatonin MT 2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology Stefano Comai, PhD; Gabriella Gobbi, MD, PhD Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University and McGill University Health Centre, Montréal, Que., Canada Background: Melatonin (MLT) is a pleiotropic neurohormone controlling many physiological processes and whose dysfunction may contribute to several different diseases, such as neurodegenerative diseases, circadian and mood disorders, insomnia, type 2 diabetes and pain. Melatonin is synthesized by the pineal gland during the night and acts through 2 G-protein coupled receptors (GPCRs), MT 1 (MEL1a) and MT 2 (MEL1b). Although a bulk of research has examined the physiopathological effects of MLT, few studies have investigated the selective role played by MT 1 and MT 2 receptors. Here we have reviewed current knowledge about the implications of MT 2 receptors in brain functions. Methods: We searched PubMed, Web of Science, Scopus, Google Scholar and articles reference lists for studies on MT 2 receptor ligands in sleep, anxiety, neuropsychiatric diseases and psychopharmacology, including genetic studies on the MTNR1B gene, which encodes the melatonin MT 2 receptor. Results: These studies demonstrate that MT 2 receptors are involved in the pathophysiology and pharmacology of sleep disorders, anxiety, depression, Alzheimer disease and pain and that selective MT 2 receptor agonists show hypnotic and anxiolytic properties. Limitations: Studies examining the role of MT 2 receptors in psychopharmacology are still limited. Conclusion: The development of novel selective MT 2 receptor ligands, together with further preclinical in vivo studies, may clarify the role of this receptor in brain function and psychopharmacology. The superfamily of GPCRs has proven to be among the most successful drug targets and, consequently, MT 2 receptors have great potential for pioneer drug discovery in the treatment of mental diseases for which limited therapeutic targets are currently available. Introduction Melatonin (MLT) is a neurohormone synthesized from serotonin (5-HT) and secreted foremost by the mammalian pineal gland following a distinct circadian rhythm with the acrophase during the dark phase and the nadir during the light phase in both diurnal and nocturnal species. 1 A typical human adult s average daytime and nighttime levels of blood MLT are approximately 10 pg/ml and 60 pg/ml, respect - ively. 2 Its production is controlled through the suprachiasmatic nucleus (SCN) by the photoperiod, peaking at night and dropping during the day. Melatonin is involved in numerous physiologic processes, including circadian rhythms, mood regulation, anxiety, sleep, appetite, immune responses and cardiac functions. 3,4 Most of the effects of MLT in the brain result from the activation of 2 high-affinity G-protein coupled receptors (GPCRs), MT 1 and MT 2. 5 Of note, GPCRs have a proven history of being excellent therapeutic targets. Recent market analyses indicate that 40% 50% of modern drugs and almost 25% of the top 200 best-selling drugs target GPCRs. 6 In addition to these high-affinity MLT receptors, another low-affinity MLT binding site, MT 3, has recently been characterized as an MLT-sensitive form of the human enzyme quinone reductase 2. 7 The functional characterization of MT 1 and MT 2 receptors in target tissues is hampered by the paucity of selective MT 1 and MT 2 receptor ligands. Structural Correspondence to: G. Gobbi, Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, 1033 Pine Ave. W, room 220, Montréal QC H3A 1A1; J Psychiatry Neurosci 2014;39(1):6-21. Submitted Jan. 14, 2013; Revised Mar. 31, 2013; Accepted Apr. 12, DOI: /jpn Canadian Medical Association 6 J Psychiatry Neurosci 2014;39(1) Role of melatonin MT 2 receptors in sleep, anxiety and other neuropsychiatric diseases determinants that confer MT 1 or MT 2 binding selectivity have only recently been elucidated. 8,9 Therefore, only a few select - ive ligands have been reported in the literature, especially with respect to MT 1 receptors; none of these ligands has been tested in vitro in cells or tissues expressing MLT receptors, and their efficacy in the treatment of neuropsychiatric diseases has been poorly evaluated. Other effects of MLT described in the literature include its neuroprotective, antiinflammatory, 13,14 pain modulatory, 15 retinal, 16 vascular, antitumour 20 and antioxidant 21 properties. Melatonin and its receptor: state of the art Who s who? Two subtypes of mammalian MLT receptors have been cloned and characterized, the MT 1 (Mel1a) and the MT 2 (Mel1b) receptor subtypes. Both subtypes are members of the 7- transmembrane GPCR family (for detailed information on the molecular properties of MLT receptors please refer to the review by Dubocovich and colleagues 5 ). By using recombinant MLT receptors it has been shown that the MT 1 receptor is coupled to different G proteins that mediate adenylyl cyclase inhibition by a pertussis toxin-sensitive G protein and phospholipase C β activation. 22 The MT 2 receptor is also coupled to inhibition of adenylyl cyclase, and it also inhibits the soluble guanylyl cyclase pathway. 23 Interestingly, the human MT 2 receptor has a lower affinity for 125 I-Mel than the human MT 1 receptor. 24 Another interesting difference between MT 1 and MT 2 receptors is that MT 2, unlike MT 1, desensitizes after exposure to the full agonist MLT, 25 likely by an internalization mechanism, but it is not clear whether this occurs after short- (minutes) or long-term (5 8 hours) exposure to MLT in vivo. 26 Based on these considerations, it appears reasonable that the use of an MT 2 receptor partial agonist might be the best approach to activate a receptor that desensitizes after exposure to its full agon - ist. Now that selective MT 2 receptor partial agonists are available, this hypothesis warrants further investigation. Where are they? The distribution of MLT receptors within the central nervous system has not been completely elucidated, primarily owing to the lack of selective antibodies for MLT receptors. The study of MLT receptor localization has mostly been performed using receptor autoradiography with the nonselect - ive 2-[ 125 I]iodomelatonin, or through real-time quantitative reverse transcription polymerase chain reaction (RT-PCR), marking the MLT receptor mrna. Messenger RNA expression of MT 1 and MT 2 receptors has been observed in the retina, SCN, thalamus, hippocampus vestibular nuclei and cerebral and cerebellar cortex At the level of the hippocampus, MT 2 receptors were detectable in particular on CA 3 and CA 4 pyramidal neurons, which receive glutamatergic excitatory inputs from the entorhinal cortex, whereas MT 1 receptors were predominantly expressed in CA Recently, using polyclonal antibodies 32 we have pointed out the presence of MT 2 receptors in the reticular thalamus, substantia nigra (pars reticulata), supraoptic nucleus, red nucleus and CA 2 and CA 3 areas of the hippocampus. 33 Using in situ hybridization histochemistry with selective and specific digoxigenin-labelled antisense and sense oligonucleotide probes, a robust hybridization of MT 1 and MT 2 receptor mrna has been observed in the SCN. 34 In humans, MT 2 receptors have been recently localized at the level of the SCN, the supraoptic nucleus and the para - ventricular nucleus using polyclonal specific antibodies. Import antly, the receptors were confined to neurons and nerve fibres, but not to glial cells. 35 What are their roles? The functional characterization of MLT receptors is still an active matter of research. It is known that MT 1 and MT 2 receptors could have either opposing or complementary functions. For example, in hippocampal slices, MT 1 and MT 2 receptor activation appears to differentially modulate γ-aminobutyric acid (GABA) A receptor function, suggesting that MLT, through activation of different receptor subtypes, may exert opposite effects in the same brain area. 36 Similarly, MT 1 and MT 2 receptors have also been shown to act in an opposite manner on the vascular system, producing vasoconstriction or vasodilatation, respectively. 18 Controversial results using in vitro and in vivo techniques have been published concerning the role of MT 1 and MT 2 receptors in circadian regulation and sleep. As mentioned previously, the mammalian SCN is known to be rich in both MT 1 and MT 2 receptors. 37 The SCN is the master clock that controls behavioural, metabolic and physiologic rhythms, 38 including the light-dependent synthesis and release of MLT from the pineal gland. 39 In vitro experiments using ligands toward MLT receptors and SCN slices from wild-type and MLT receptor knockout mice showed that activation of MT 1 receptors inhibited the neuronal firing rate of the SCN, whereas activation of MT 2 receptors phase-shifted circadian rhythms of neuronal firing rates. 26,34,37,40,41 But, in Siberian hamsters in which the MT 1 receptor was functional, but the MT 2 receptor was not, MLT elicited a clear phase shift of the circadian rhythm of SCN electrical activity. 42 In vivo experiments in MLT receptor knockout mice further complicated the scenario. Dubocovich and Markowska, 26 injected MLT 2 hours before the onset of activity in mice kept under constant darkness and found a phase shift in the activity onset in wild-type but not in MT 1 receptor knockout (MT / 1 ) mice. Moreover, MLT accelerated the entrainment to a new light dark cycle of wild-type, but not of MT / 1 mice. For these reasons, current knowledge does not allow us to rule out a possible role of MT 1 receptors in the phase shift of SCN neuronal activity due to MLT. 37,43 Selective MT 2 receptor ligands used in preclinical psychopharmacological and neurobiological studies Melatonin, through activation of MT 1 and MT 2 receptors, modulates and controls several brain functions; however, J Psychiatry Neurosci 2014;39(1) 7 Comai and Gobbi owing to the lack of selective MT 1 and MT 2 receptor ligands and a paucity of behavioural studies in MT 1 / and MT 2 receptor knockout (MT 2 / ) mice, little was known regarding the functional role of these receptors. Recently, some selective MT 2 receptor ligands have been designed and synthesized, allowing researchers to explore the role of MT 2 receptors in brain functions. In the last decade, efforts have been made to develop se - lect ive MT 1 or MT 2 receptor agonists. 9 A great number of li - gands highly selective for the MLT receptors have been recently developed, but these advances have been met with difficulty obtaining compounds with selectivity toward only 1 of the 2 MLT receptor subtypes. Very few selective MT 1 receptor agonists have been reported until now. 8 On the contrary, since structure activity relationships for the binding at the MT 2 receptor are quite consolidated, 44 several MT 2 receptor ligands belonging to different chemical classes have been developed (for more details, see the reviews by Mor and colleagues 9 and Zlotos 45 ). Only a very limited number of these selective MT 2 receptor agonists/antagonists have been tested in preclinical psychopharmacology tests and in neurobio - logic al studies aimed at dissecting the role of MT 2 receptors in brain function. Specifically, as revealed by the research we review here, only 4 selective MT 2 receptor ligands have been tested: the MT 2 partial agonist UCM765, 44 the MT 2 full agonist IIK7, 46 and the MT 2 antagonists 4-phenyl-2-propionamido - tetralin (4P-PDOT) 47 and K Figure 1 shows the chemical structure and the binding affinity of these ligands to the human MT 1 and MT 2 receptors. The partial agonist UCM765 belongs to the N-(Substitutedanilinoethyl) amides, a class of compounds that, depending on the type and size of substituents to the aniline nitrogen, may lead to a different degree of selectivity and intrinsic activity toward MT 1 or MT 2 receptors. 44 Even though the indole MT2 receptor agonists UCM765, partial agonist mt1 receptor pki = 8.38 MT2 receptor pki = IIK7, full agonist mt1 receptor pki = 8.34 MT2 receptor pki = Melatonin mt1 receptor pki = 9.85 MT2 receptor pki = 9.62 MT2 receptor antagonists 4P-PDOT mt1 receptor pki = 6.3 MT2 receptor pki = 8.8 K-185 mt1 receptor pki = 7.18 MT2 receptor pki = 9.30 Fig. 1: MT 2 receptor ligands used in psychopharmacological studies. Binding affinity constants have been assessed on the recombinant human MT 1 and MT 2 receptors expressed in NIH3T3 cells for melatonin, 44 UCM765, 44 IIK7 and K and in COS-7 cells for 4-phenyl-2-propionamidotetralin (4P-PDOT) J Psychiatry Neurosci 2014;39(1) Role of melatonin MT 2 receptors in sleep, anxiety and other neuropsychiatric diseases ring of MLT is not essential for binding to the MT 1 and MT 2 receptors, IIK7 is a 6H-Isoindolo[2,1-a]indoles derivative whereas K-185 is a 6,7-Dihydro-5H-benzo[c]azepino[2,1-a] indoles derivative. Substituents in ortho position to the indole nitrogen of MLT, such as a phenyl ring, have been shown to increase binding affinity as well as potency to MT 1 and MT 2 receptors with respect to MLT itself. Interestingly, changes in the ring size that bridges the indole to the phenyl ring greatly affect the potency of these compounds; IIK7 with a 5 atoms ring is a full agonist, whereas K-185 with a 7 atoms ring is an antagonist. 46 The antagonist 4P-PDOT is a tetralin derivative with antagonist properties and high selectivity toward MT 2 receptors (300-fold higher than the MT 1 receptor). 47 Of note, even though at the present moment it is the most used MT 2 receptor antagonist, it should always be kept in mind that depending on the assay and the concentration, 4P- PDOT may also act as a weak partial agonist. 48 Both UCM765 and IIK7 have been studied in vivo for their potential sleeppromoting properties in rats. When compared with MLT, both of these compounds showed higher affinity for the MT 2 receptor (Fig. 1). Importantly, while UCM765 is an MT 2 partial agonist (α = 0.6) that possesses 100-fold higher affinity for MT 2 than MT 1 receptors, 33,44 IIK7 is an MT 2 full agonist with 90-fold higher affinity for MT 2 than MT 1 receptors. 49 Even though experiments comparing the sleep-promoting properties of the 2 compounds have not yet been conducted, it is important to remember that partial agonists, thanks to their flexible properties compared with full agonists, are becoming more and more popular in psychopharmacology. 50 They are intelligent drugs since they can activate receptors to give a desired submaximal response when inadequate amounts of the endogenous ligand are present, or they can reduce the overstimulation of receptors when excess amounts of the endogenous ligand are present, thus acting as competitive antagonists. 51 Several other selective MT 2 receptor ligands, such as 1,6- Dihydro-2H-indeno[5,4-b]furan, 52 N-[3-(3-methoxyphenyl) propyl] amide, 53 phenylpropylamide 54 and 2-(phenylthio) benzo [b] thiophene 55 derivatives, have recently been develop - ed, and according to the literature reviewed herein, they warrant further examination in preclinical psychopharmacology tests. MT 2 receptors and sleep In mammals, normal sleep is characterized by an orderly progression from wakefulness to non rapid eye movement sleep (NREMS) and to rapid eye movement sleep (REMS). Wakefulness is characterized by low voltage, fast electroencephalogram (EEG) activity and high muscle tone with phasic electromyogram (EMG) activity. Non rapid eye movement sleep is characterized by high voltage, slow EEG activity and reduced muscle tone, with characteristic high-voltage slow waveforms (1 4 Hz, waves), sleep spindles, and K- complexes. Rapid eye movement sleep, or paradoxical sleep (PS), is characterized by low-voltage, fast EEG activity with an absence of muscle tone and a pronounced θ rhythm (4 9 Hz). The deep stages of NREMS (stages 3 and 4) are also known as slow-wave sleep (SWS), which is thought to be the most restorative sleep stage. 56 During SWS, several physiologic processes, such as memory consolidation, metabolic regulation, and drop in blood pressure, 63 occur. In people with major depression, secondary insomnia is frequent, with alterations in sleep neurophysiology, notably decreased SWS, reduced REMS latency and increased REMS density. Increased REMS density has also been observed in people with eating disorders, narcolepsy, presenile dementia and other neuropsychiatric diseases. 64 Melatonin and sleep In rats, contradictory effects of MLT in sleep have been reported. Holmes and Sugden 65 reported that MLT reduces time to sleep onset and increases both SWS and PS. Others suggest that MLT is involved only in the control of PS regulation since the lesion of the pineal gland or inhibition of MLT synthesis using a β-adrenergic antagonist (propranolol) decreased PS during light and dark periods. 66,67 Melatonin (2.5 mg/kg and 5 mg/kg) increased the number of sleep cycles and the total duration of PS, 68 and at the dose of 10 mg/ kg, MLT decreased the onset to the first episode of SWS and increased the duration of SWS and PS. These latter effects were blocked by the GABA A antagonists flumazenil and picrotoxin. 69 In monkeys, MLT (0.3, 1 and 3 mg/kg) does not affect SWS, REMS and light sleep, but does shorten the latency to the first episode of sleep. However, this reduction in the latency to sleep occurred only at the lowest dose. 70 In a study using rats, 71 MLT affected neither sleep nor circadian rest activity rhythms. In cats, exogenous MLT ( mg/ kg) significantly increased SWS, but the effect was weak and lasted for only 2 hours. 72 There is a large body of research demonstrating hypnotic effects of MLT in clinical studies, although some studies failed to find significant effects, 78,79 and therefore its clinical efficacy is still unclear. 80 These discrepant results may origin - ate from the pharmacological constraints of generic MLT, limiting its clinical use: short half-life ( 1 hr), high first-pass metabolism, binding of multiple receptors and effects dependent on time of the day or phase of circadian rhythm. 81 For example, the hypnotic effect of MLT in humans varies depending on the time of the administration, consistent with the circadian phase resetting properties of MLT. 82 Although several studies suggest that MLT treatment may be ap - propriate for sleep disorders, it is not established whether MLT acts directly on sleep regulation or on circadian rhythms associated with sleep. However, the sleep pro - moting effect of the MT 1 /MT 2 receptor agonist ramelteon (TAK-375) strongly suggests that MLT compounds facilitate the induction of sleep rather than modify all sleep architecture or circadian rhythms. Ramelteon has been approved by the U.S. Food and Drug Administration (July 2005) for the treatment of insomnia characterized by difficulty with sleep onset. 83 Given that ramelteon is an MLT receptor agonist with high affinity for both MT 1 and MT 2 receptors, it is difficult to dissect the receptor subtype(s) involved in its sleeppromoting properties. J Psychiatry Neurosci 2014;39(1) 9 Comai and Gobbi MT 2 receptor ligands (UCM765 and IIK7) and sleep The pharmacological studies using selective MT 2 receptor ligands have allowed researchers to better identify the role of the MT 2 receptor in sleep function. Since MLT synthesis, and thus its circulating levels as well as the expression of its receptors, follow circadian daily variations, sleep experiments with UCM765 were performed across the entire 24-hour sleep wake cycle to examine its effects across the light dark period. 33 Given the short half-life of the compound (T 1/2 = 44 min) due to an extensive first-pass metabolism, 33,84 UCM765 was injected every 4 hours to keep the concentration of the drug within the steady state range
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