6 ^th European Biopharma Congress September 18-19, 2018 Amsterdam, Netherlands

Jana Tchekalarova has completed her PhD in pharmacology in 2004 from Institute of Physiology, BAS. She has 22 years of research experience. Current position - Assoc Professor at the Institute of Neurobiology, BAS, Head of “Behavioral neurobiology” Dept. An Adjunct Professor at the Section of Biochem, Physiol Pathophysiol in the Med Dept Sofia University. According to Mendeley profile: h-index = 12, publications 51 with IF; citations = 385. More than than 500 citations. She has been serving as an editorial board member of Drug Dev Res, J Neurol Dis Stroke and Asian Counc Sci Editors.

The majority of available literature on experimental animals revealed that melatonin has anticonvulsant action in acute seizures tests with different mechanism of action. An important advantage of melatonin as an add-on option in a therapy of epilepsy is associated with its low toxiticy, antioxidant activity as well as its ability to synchronize disturbed circadian rhythms in epileptic patients. A series of melatonin analogues, containing indole scaffold, were synthesized and their anticonvulsant activity was tested on ICR mice by measuring the time of three different seizure phases (myoclonic, clonic and tonic) induced by intravenous infusion of pentylenetetrazol (PTZ). The novel melatonin derivatives were synthesized according to the classical method by condensation of hydrazones with 5-methoxyindole-3-carboxaldehyde or 5-benzyloxyindole-3-carboxaldehyde. The hydrazide-hydrazones with indole moyeties were purified by recristalization and the molecular weights were determined, using ES-MS. The compounds were injected intraperitoneally at doses of 30, 60 and 100 mg/kg 30 min before PTZ. The most potent compounds, with significantly increased thresholds for myoclonic, clonic and tonic seizures compared to vehicle were the derivatives with 2-thienyl and p-Cl-phenyl fragments at a dose of 60 mg/kg, which effects was comparable to that of melatonin at the same dose of 60 mg/kg, used as a positive control. None of the compounds displayed neurotoxicity in the rota-rod test. In silico assessment of their BBB permeability indicated them as CNS active agents. Ðœolecular docking was performed into a human gamma-aminobutyric acid (GABAA) receptor and depicted good binding properties of melatonin derivatives, considered in this study. Based on anticonvulsant screening results these newly synthesized melatonin derivatives will be explored in other seizure tests with different mechanism of action as well as in models of epilepsy. Application grant: National Science Fund of Bulgaria

Violina T. Angelova has completed her PhD in organic chemistry in 2004 from Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Science. She has 22 years of research experience and published more than 29 papers in reputed journals. Current position - Assoc Professor at the Faculty of Pharmacy, Medical University of Sofia.

Melatonin receptor (MT1) is an attractive target for elaboration of new drug candidates, but unfortunately is known to be unstable out of the membrane lipid bilayer which makes the obtaining of a crystal structure by X-Ray diffraction (XRD) an elusive goal. Up to now there is no published real structure, suitable for docking of new ligands targeting this receptor. However, there are lots of models based on the data from crystallized rhodopsin, but they are too artificial for reasonable docking of drug-like candidate molecules. To overcome these drawbacks we built an in silico molecular model of a melatonin receptor in membrane bilayer in water cell, with explicit water molecules. For that purpose we used GROMACS molecular mechanics software with GROMOS force field and TYP3P water model. Calculations were carried out in periodic boundary conditions at 300 K and 1 bar pressure, physiological NaCl content and pH 7. By the simulation we caught the act of melatonin entering the receptor which enlightened a wide variety of interactions that can facilitate or to disturb the movement of melatonin to the hardly accessible active site of MT1. Ðœolecular docking of the drug like candidates was performed on receptor model. The information can be used along with data obtained from the structure of melatonin-receptor complex to construct new analogs of melatonin, capable not only to activate the receptor but also to successfully manage their way to the MT1 binding site.