Melatonin antagonists

Figure 5.10. Ligand-based virtual screening/similarity analysis of a 150,000-compound database containing about 250 known melatonin antagonists, showingthe strong performance of the pharmacophore descriptors, and the complementarity of atom pairs and pharmacophore descriptors when combined.

Jacobsen Epoxidation, Sharpless Dihydroxyiation (Bristol-Myers Squibb). Both, Jacobsen and Sharpless methodology were applied for making multikilogram amounts of benzofuran epoxide, an intermediate for a melatonin antagonist (82). Both reactions required extensive optimization of reagents and reaction conditions. 

Melatonin [73-31-4] C 2H N202 (31) has marked effects on circadian rhythm (11). Novel ligands for melatonin receptors such as (32) (12), C2yH2gN202, have affinities in the range of 10 Af, and have potential use as therapeutic agents in the treatment of the sleep disorders associated with jet lag. Such agents may also be usehil in the treatment of seasonal affective disorder (SAD), the depression associated with the winter months. Histamine (see Histamine and histamine antagonists), adenosine (see Nucleic acids), and neuropeptides such as corticotropin-like intermediate lobe peptide (CLIP) and vasoactive intestinal polypeptide (VIP) have also been reported to have sedative—hypnotic activities (7). 

LY 156735 is a [1-substituted analog of melatonin that has greater bioavailability than melatonin (Nickelsen et al. 2002). It is in an earlier stage of clinical trials in initial trials, it reduced the sleep onset time in patients with moderate sleep-onset insomnia. Several other specific melatonin receptor agonists and antagonists are in development (Rivara et al. 2005 Zlotos 2005) and presumably will be clinically tested over the next few years. 

The monoamine hypothesis, like the neurotrophic hypothesis, is at best incomplete. Many studies have not found an alteration in function or levels of monoamines in depressed patients. In addition, some candidate antidepressant agents under study do not act directly on the monoamine system. These include glutamate antagonists, melatonin agonists, and glucocorticoid-specific agents. Thus, monoamine function appears to be an important but not exclusive factor in the pathophysiology of depression. 

This case raises an important question regarding the dopamine-blocking effect of melatonin. Like dopamine receptor antagonists, melatonin should be used with care, because of the risk of tardive dyskinesia, which has serious morbidity and a low remission rate. Melatonin should be used with special caution in patients with organic brain damage. 

The G-protein coupled receptors modulate intracellular cAMP level, which plays a crucial role in epidermal barrier homeostasis.5 Increase of intracellular cAMP in epidermal keratinocytes by topical application of forskolin delays barrier recovery, while cAMP antagonists accelerate the barrier recovery. Activation of dopamine 2-like receptors (manuscript in preparation), melatonin receptors, or serotonin receptor (type 5-HT1) decreases intracellular cAMP and consequently accelerates the barrier recovery (Figure 15.1), while activation of adrenergic 32 receptors increases intracellular cAMP and delays the barrier repair.6 Barrier disruption induces an increase of the intracellular cAMP level. Thus, topical application of agonists of receptors that reduce intracellular cAMP accelerates the barrier repair. Our results are summarized in Table. 15.1. 

Yamamoto, H.-A., Tang, H.-W. (1996). Antagonistic effect of melatonin against cyanide-induced seizures and acute lethality in mice. Toxicol. Lett. 87 19-24. 

Tetrahydronaphthalenic derivatives (new agonist and antagonist ligands for melatonin receptors)... 

Lutrepulse gonadotrophin-releasing hormone, lutropin luteinizing hormone, luzindole (N-acetyl-2-benzyltryptamlne N 0774) is a melatonin receptor antagonist (with moderate selectivity for MeljB over the Meli subtype). It shows ANTIDEPressant-like activity in animal model. 

It seems very likely that there are important advances to be made in the application of melatonin agonists to the modification of sleep states and circadian rhythms. See also MELATONIN RECEPTOR ANTAGONISTS. 

Garratc. P.J. etai (1995) Mapping the melatonin receptor. 3. Design and synthesis of melatonin agonists and antagonists derived from 2-phenyltryptamines. 

---