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Research Article

Potent Lipophilic Melatoninergic <i>x</i>-fluoro-<i>y</i>-methoxy Substituted Phenylalkylamides: Molecular Dynamics Calculations and <i>in vitro</i> Modified Release in Aqueous Media from Tablet Formulations

[ Vol. 29 , Issue. 17 ]


Marilena Vlachou*, Angeliki Siamidi, Dionysia Anagnostopoulou, Chrystalla Protopapa, Rodoula Kompogennitaki, Aikaterini Sakellaropoulou, Natasa Efstathiou, Ioannis Papanastasiou, Maria Billia and Thomas Mavromoustakos   Pages 1370 - 1378 ( 9 )


Introduction: We report herein on the design and development of matrix tablets containing potent synthetic melatonin (MLT) receptor analogues, the x-fluoro-y-methoxy substitiuted phenylalkylamides (compounds I-IV), the preparation and melatoninergic potency of which was recently communicated.

Methods: The presence of the fluorine atom in compounds I-IV, besides not affecting their binding affinity, compared to the pineal hormone melatonin, it also slows down their metabolism, which is a major drawback of MLT. However, as fluorine increases the lipophilicity, solid pharmaceutical formulations of I-IV, involving the appropriate biopolymers for their modified release in aqueous media, were developed in the context of the present work.

Results: The release profile of analogues I-IV was found to be similar to that of MLT and also of the commercially available drug, Circadin®. Some of these systems are suitable for dealing with sleep onset problems, whilst others for dealing with combined sleep onset/sleep maintenance problems.

Conclusion: Apart from the nature and relevant content of the formulants used, this bimodal release profile of the new analogues depends, to a large extent, on the diverse structural arrangement of their side chains in space, as nicely demonstrated by the molecular dynamics calculations, conducted in the context of this study.


Melatonin, synthetic melatoninergics, tablets, dissolution, drug release, molecular dynamics calculations.


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