Melatonergic drugs in development

Abstract

Melatonin (N-acetyl-5-methoxytryptamine) is widely known as “the darkness hormone”. It is a major chronobiological regulator involved in circadian phasing and sleep-wake cycle in humans. Numerous other functions, including cyto/neuroprotection, immune modulation, and energy metabolism have been ascribed to melatonin. A variety of studies have revealed a role for melatonin and its receptors in different pathophysiological conditions. However, the suitability of melatonin as a drug is limited because of its short half-life, poor oral bioavailability, and ubiquitous action. Due to the therapeutic potential of melatonin in a wide variety of clinical conditions, the development of new agents able to interact selectively with melatonin receptors has become an area of great interest during the last decade. Therefore, the field of melatonergic receptor agonists comprises a great number of structurally different chemical entities, which range from indolic to nonindolic compounds. Melatonergic agonists are suitable for sleep disturbances, neuropsychiatric disorders related to circadian dysphasing, and metabolic diseases associated with insulin resistance. The results of preclinical studies on animal models show that melatonin receptor agonists can be considered promising agents for the treatment of central nervous system-related pathologies. An overview of recent advances in the field of investigational melatonergic drugs will be presented in this review.

Pathophysiological and pharmacological modulation of melatonergic system

“…Based on the on evidence-based treatment of insomnia, parasomnia, and circadian rhythm sleep disorders, the British Association for Psychopharmacology concluded that melatonin is the first-choice treatment when a hypnotic is indicated in patients aged more than 55 years. 1,11,12,[14][15][16] A recent post-marketing surveillance study conducted by Hajak et al, 17 also proved the efficacy of the prolonged-release melatonin, circadin.…”

“…The gene coding for AANAT is directly influenced by the photoperiod and also the mRNAs encoding for these enzymes involved in the synthetic pathway of melatonin are expressed with a day/night rhythm. 1,6,7 As discussed above melatonin biosynthesis is synchronized to the light/dark cycle by the suprachiasmatic nucleus (SCN). SCN, the internal "biological clock," gets photic input from the external environment via the retinohypothalamic tract.…”

“…And also there are no next-day hangover effects or withdrawal effects (rebound insomnia) associated with ramelteon, even at higher doses. 1,14,27,28 …”

Synchrony and desynchrony in circadian clocks: impacts on learning and memory

“…Readily passing through the blood brain barrier, melatonin increases daytime sleep duration with little effect on sleep latency for night-shift workers (Sharkey et al 2001;Liira et al 2015) and phase-shifts circadian rhythms in simulated night-shift studies . During the day, the circadian system maintains arousal in the face of increased time awake with decreased arousal at night due, in part, to rising melatonin levels which target MT 1 and MT 2 receptors in the SCN to dampen SCN driven arousal signals (Dodson and Zee 2010;Carocci et al 2014). Melatonin is used as a treatment of circadian perturbations including jet lag, shift work, or delayed sleep disorder (PandiPerumal et al 2008;Brown et al 2009;Srinivasan et al 2010) and can be used in combination with bright light therapy, to accelerate reentrainment for jet lag (Dodson and Zee 2010;Zee and Goldstein 2010).…”

“…Melatonin is used as a treatment of circadian perturbations including jet lag, shift work, or delayed sleep disorder (PandiPerumal et al 2008;Brown et al 2009;Srinivasan et al 2010) and can be used in combination with bright light therapy, to accelerate reentrainment for jet lag (Dodson and Zee 2010;Zee and Goldstein 2010). Newly developed selective MT 1 /MT 2 receptor agonists (Srinivasan et al 2010;Carocci et al 2014) include Ramelteon which effectively acts as a phase shifting agent in humans (Richardson et al 2008;Carocci et al 2014) and animal models (Rawashdeh et al 2011) as well as Tasimelteon which facilitates entrainment to a 24-h cycle maintaining melatonin rhythms, sleep latency, and sleep quality (Carocci et al 2014;Neubauer 2015). (4) The use of wakefulness promoting drugs to increase arousal and performance in circadian disorders include caffeine and modafinil.…”