Indolic melatonin agonists

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Melatonin has been studied extensively as described above and many close indole containing analogs have also been reported in the literature. The melatonin agonist LY-156735,2 was recently reported to alleviate the symptoms of shift lag and to help resynchronize circadian rhythms at a dose of 5 mg/day in human clinical trials [53].

Indole derivative 3, with 5-fold greater potency than melatonin was recently described [57]. The group also reported the synthesis and biological evaluation of tricyclic melatonin analogs with alkyl and cycloalkyl groups in the beta position of the ethylamido chain [58]. When two beta methyl groups were added to the side-chain of the methoxyl-substituted ligand, 4 an increase in agonist potency was observed. However, more bulky R group beta-substituents, reportedly led to antagonism.

Recently sulfur analogs of melatonin, 5 and 6 were reported to have decreased binding affinity at human MT1 and MT2 receptors combined with reduced potency as melatonin agonists [59]. Introduction of the sulfur at the 5 position as seen in 5 resulted in a 35-fold reduction in binding to MT1 and 44-fold reduction in binding to MT2 compared to Melatonin. The thioamide 6 gave a 2.5- and 2-fold reduction in binding affinity for MT1 and MT2, respectively, indicating the greater importance of the 5-methoxy group to receptor affinity.

Computational methods have also been used to help determine the active conformation of melatonin and the structural requirements for both melatonin receptor subtype specificity and intrinsic activity. In a recent report ab initio calculations were used to analyze the conformation of melatonin and the results were used to explain the different receptor affinities and subtype specificity of various melatonin analogs with restricted conformations [60,61]. Three dimensional quantitative structure-activity relationship comparative molecular field analysis (3D-QSAR CoMFA) was also recently reported with further exploration of the structural requirements for the melatonin receptor subtypes and intrinsic activity modulation [62].

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