I am interested in information on clinical effects of melatonin receptor ligands.

Bedini A, Spadoni G, Gatti G, Lucarini S, Tarzia G, Rivara S, Lorenzi S, Lodola A, Mor M, Lucini V, Pannacci M, Scaglione F.

Design and Synthesis of N-(3,3-Diphenylpropenyl)alkanamides as a Novel Class of High-Affinity MT(2)-Selective Melatonin Receptor Ligands.
J Med Chem. 2006 Dec 14;49(25):7393-7403.

A novel series of melatonin receptor ligands was discovered by opening the cyclic scaffolds of known classes of high affinity melatonin receptor antagonists, while retaining the pharmacophore elements postulated by previously described 3D-QSAR and receptor models. Compounds belonging to the classes of 2,3- and [3,3-diphenylprop(en)yl]alkanamides and of o- or [(m-benzyl)phenyl]ethyl-alkanamides were synthesized and tested on MT1 and MT2 receptors. The class of 3,3-diphenyl-propenyl-alkanamides was the most interesting one, with compounds having MT2 receptor affinity similar to that of MLT, remarkable MT2 selectivity, and partial agonist or antagonist behavior. In particular, the (E)-m-methoxy cyclobutanecarboxamido derivative 18f and the di-(m-methoxy) acetamido one, 18g, have sub-nM affinity for the MT2 subtype, with more than 100-fold selectivity over MT1, 18f being an antagonist and 18g a partial agonist on GTP&ggr;S test. Docking of 18g into a previously developed MT2 receptor model showed a binding scheme consistent with that of other antagonists. The MT2 expected binding affinities of the new compounds were calculated by a previously developed 3D-QSAR CoMFA model, giving satisfactory predictions.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17149869&query_hl=2&itool=pubmed_docsum

Tsotinis A, Vlachou M, Papahatjis DP, Calogeropoulou T, Nikas SP, Garratt PJ, Piccio V, Vonhoff S, Davidson K, Teh MT, Sugden D.

Mapping the melatonin receptor. 7. Subtype selective ligands based on beta-substituted N-acyl-5-methoxytryptamines and beta-substituted N-acyl-5-methoxy-1-methyltryptamines.
J Med Chem. 2006 Jun 15;49(12):3509-19.

A series of beta-substituted and beta,beta-disubstituted N-acyl 5-methoxy-1-methyltryptamines and 5-methoxytryptamines have been prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor. The affinity of analogues was determined in a radioligand binding assay using cloned human MT(1) and MT(2) receptor subtypes expressed in NIH 3T3 cells. Agonist and antagonist potency of all analogues was measured using the pigment aggregation response of a clonal line of Xenopus laevis melanophores. beta-Methylmelatonin (17a) and beta,beta-dimethylmelatonin (17b), though showing a slight decrease in binding at human receptors, show an increase in potency on Xenopus. N-Butanoyl 5-methoxy-1-methyl-beta,beta-trimethylenetryptamine (12c) is an antagonist at human MT(1) receptors but an agonist at MT(2), while N-butanoyl 5-methoxy-1-methyl-beta,beta-tetramethylenetryptamine (13c) is an antagonist at MT(1) but had no action at MT(2) and is one of the first examples of an MT(1) selective antagonist.

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Delagrange P, Boutin JA.

Therapeutic potential of melatonin ligands.
Chronobiol Int. 2006;23(1-2):413-8. Review.

Melatonin is a neurohormone that is believed to be involved in a wide range of physiological functions. In humans, appropriate clinical trials confirm the efficacy of melatonin or melatoninergic agonists for the MT1 and MT2 receptor subtypes in circadian rhythm sleep disorders only. Nevertheless, preclinical animal model studies relevant to human pathologies involving validated reference compounds lead to other therapeutic possibilities. Among these is a recently developed treatment concept for depression, which has been validated by the clinical efficacy of agomelatine, an agent having both MT1 and MT2 agonist and 5-HT2C antagonist activity. A third melatonin binding site has been purified and characterized as the enzyme quinone reductase 2 (QR2). The physiological role of this enzyme is not yet known. Recent results obtained by different groups suggest: (1) that inhibition of QR2 may lead to "protective" effects and (2) that over-expression of this enzyme may have deleterious effects. The inhibitory effect of melatonin on QR2 observed in vitro may explain the protective effects reported for melatonin in different animal models, such as cardiac or renal ischemia-effects that have been attributed to the controversial antioxidant properties of the hormone. The development of specific ligands for each of these melatonin binding sites is necessary to link physiological and/or therapeutic effects.

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den Boer JA, Bosker FJ, Meesters Y.

Clinical efficacy of agomelatine in depression: the evidence.
Int Clin Psychopharmacol. 2006 Feb;21 Suppl 1:S21-4.

Despite the advances of recent decades, there is still an urgent need for antidepressants with improved efficacy, safety and tolerability. Agomelatine is a new antidepressant with an innovative pharmacological profile. It is the first melatonergic antidepressant, and is a potent agonist of melatonin receptors (MT1 and MT2) with 5-HT2C antagonist properties. The efficacy of 25 mg/day agomelatine in treating major depressive disorder (MDD) has been demonstrated in a number of placebo-controlled studies. Evidence of improvement in depressive symptoms was observed in a dose-ranging study in which 25 mg/day agomelatine was significantly better than placebo, whatever the rating scale used (Hamilton Rating Scale for Depression, Clinical Global Impression, and Montgomery-Asberg Depression Rating Scale). These results have been confirmed in two similarly designed placebo-controlled studies. Agomelatine also produces a significant improvement in anxiety compared to placebo, according to Hamilton Rating Scale for Anxiety scores. The efficacy of agomelatine has been studied in subpopulations with more severe depression, demonstrating its efficacy in these difficult-to-treat patients. In view of the available data on agomelatine, this antidepressant can be regarded as an innovative treatment for MDD patients, offering a new approach in the management of depressed patients.

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Fuchs E, Simon M, Schmelting B.

Pharmacology of a new antidepressant: benefit of the implication of the melatonergic system.
Int Clin Psychopharmacol. 2006 Feb;21 Suppl 1:S17-20. Review.

The limitations of current antidepressant medications merit the exploration of alternative agents with novel antidepressant mechanisms of action. The established clinical finding that desynchronization of internal rhythms plays an important role in the pathophysiology of depressive disorders has stimulated the idea that resetting normal circadian rhythms may have antidepressant potential. Recent experiments using the novel melatonin receptor agonist and serotonin 2 (5-HT2c) receptor antagonist agomelatine (S20098; N[2-(7-methoxy-1-naphthyl)ethyl]- acetamide) revealed a notable chronobiotic activity and clear antidepressant-like effects in a variety of preclinical models. Binding studies performed in vitro proved that agomelatine is a high-affinity agonist at both the melatonin MT1 and MT2 receptor types. In addition, these studies revealed that agomelatine, in contrast to melatonin, blocks 5-HT2c receptors with significant affinity. Antagonism of 5-HT2c receptors is reported for various established antidepressant compounds. The antidepressant properties of agomelatine are thus based on its melatonergic actions and 5-HT2c receptor antagonism.

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Erman MK.

Therapeutic options in the treatment of insomnia.
J Clin Psychiatry. 2005;66 Suppl 9:18-23; quiz 42-3. Review.

Pharmacologic and nonpharmacologic therapies both have roles in the treatment of insomnia. The benzodiazepines, when first introduced, were a major improvement over earlier treatments for insomnia in terms of their safety and efficacy. Since then, the nonbenzodiazepine benzodiazepine receptor agonists have been developed, which have provided advantages over the older medications and are currently first-line medication treatment for insomnia. Although antidepressants, antipsychotics, and anticonvulsants are often prescribed for the treatment of insomnia, they are not approved by the U.S. Food and Drug Administration for this indication and have side effects that are sometimes severe. New types of medications that have different modes of action from the benzodiazepine receptor agonists are now being developed, and one, a selective melatonin receptor agonist, has recently been approved for treatment of insomnia. Nonpharmacologic therapies can also help patients learn how to fall asleep faster and improve sleep quality. It is important for physicians to teach patients good sleep hygiene as part of their treatment. Cognitive-behavioral therapy is effective in the treatment of insomnia, alone and in combination with pharmacotherapy, but finding a qualified provider can be difficult and the patient must be willing to take the time to learn the therapies and wait for them to show effect.

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