Investigational melatonin receptor agonists.
BACKGROUND
Melatonin is a major chronobiological regulator involved in circadian phasing, sleep, and numerous other functions including cyto-/neuroprotection, immune modulation, and energy metabolism. The suitability of melatonin as a drug is limited because of its short half-life. Therefore, various indolic and non-indolic melatonergic agonists have been developed. Frequent health problems such as sleep disturbances, neuropsychiatric disorders related to circadian dysphasing, and metabolic diseases associated with insulin resistance are targeted by melatonergic agonists.


METHODS
Various synthetic melatonergic drugs are compared with regard to receptor affinities, selectivity, effects on sleep, endogenous melatonin, circadian phase and insulin-related metabolism.


RESULTS
The chemical design of melatonin receptor agonists is discussed in relation to consequences for receptor affinity, selectivity, metabolism, and spectrum of effects.


CONCLUSIONS
Melatonergic agonists are suitable for phase-shifting circadian rhythms, and may be used for treating disorders related to circadian dysfunction including sleep difficulties. Facilitation of sleep onset is a general property, whereas promotion of sleep maintenance is demonstrable but not always fully sufficient. Details are especially available for tasimelteon. Support of insulin sensitivity may become a new area of application for compounds such as NEU-P11. Some drugs acting additionally as serotonergic antagonists display antidepressant properties.
Hardeland
Rüdiger
R
University of Göttingen, Johann Friedrich Blumenbach Institute of Zoology and Anthropology, Göttingen, Germany. rhardel@gwdg.de
D000818:Animals; D002940:Circadian Rhythm / Q000187:drug effects; D015507:Drugs, Investigational / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008550:Melatonin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D044094:Receptors, Melatonin / Q000819:agonists* / Q000378:metabolism; D012890:Sleep / Q000187:drug effects; D020178:Sleep Disorders, Circadian Rhythm / Q000188:drug therapy*
D015507:Drugs, Investigational; D007328:Insulin; D044094:Receptors, Melatonin; D008550:Melatonin