Biomedical Engineering Reference
In-Depth Information
F
NH
O
F
O
F
O
N
N
N
N
N
N
F
O
S
HO
N
O
Ketanserin
Ritanserin
Eplivanserin
FIGURE 20.9
Structure of the 5-HT
2A
antagonists ketanserin, ritanserin, and eplivanserin.
the classical objective endpoints: induction and maintenance in clinical studies carried out to date.
Therefore in order to have the compounds approved, a clinically meaningful consequence of the
enhanced SWS has to be demonstrated. This means that effects on daytime performance must be
available at the time of registration. If these compounds are approved for the treatment of insomnia,
this may change the possibility for treating insomnia associated with depression or anxiety.
20.3.3 O
REXINERGICS
Under normal circumstances, a reciprocal inhibition between the wake promoting orexinergic sys-
tem and the GABAergic sleep-enhancing system exists. Preclinical experiments have demonstrated
that the endogenous peptide orexin is wake promoting. Recent interest from a number of pharma-
ceutical companies have resulted in the development of selective orexin receptor antagonists acting
at OR-1 or OR-2 receptors for the promotion of sleep. The role played by OR-1 and OR-2 receptors
in sleep is still not completely established. Preclinical data have demonstrated the hypnotic effects
of orexinergic antagonists GSK649868 and ACT-078573 (Figure 20.10). Indeed one nonselective
antagonist (ACT-078573) has been shown to promote REM and non-REM sleep in healthy human
volunteers. However, one important question is whether hyperfunction of the orexinergic system is
involved in the pathophysiology of insomnia and whether orexin-based therapies have any unwanted
side effects.
O
O
N
N
O
NH
O
NH
HN
F
N
F
F
F
F
GSK649868
ACT-078573
FIGURE 20.10
Structures of two orexinergic antagonists.
20.3.4 M
ELATONIN
AND
M
ELATONERGIC
A
GONISTS
Melatonin (Figure 20.11) is an endogenous hormone, which in response to darkness is secreted
from the pineal gland and subsequently activates the G-protein coupled melatonin receptors
(MT1-3). Activation of MT1 and 2 leads to a release of GABA in the hypothalamus and this con-
tributes to the entrainment of the circadian cycle. Melatonin is therefore a compound, which may
