METHOD OF PHARMACEUTICAL ALTERNATIVE FOR THE DEVELOPMENT OF NEW 5-HT2A-ANTAGONIST

Abstract

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In some cases while producing the new drugs using a specific method of pharmaceutical alternatives is used. This method is to optimize the performance of the initial molecules due to changes in its salt-forming components or dosage form. Previous studies at the Department of Pharmacology of Volgograd State Medical University provided the production of a a fused azoles analogue, with a signified 5-HT2A antagonist activity. However, we noted the lack of long-term storage stability, and therefore the working out of a more stable compound at room temperature became reasonable. On this basis we have synthesized dihydrochloride and dihydrobromide of the original molecule. Purpose of the work was to explore the equivalence of anti-serotonin action of various salt derivatives of a previously identified 5-HT2A antagonist. Materials and methods of the study: the investigation of 5-HT2A-activity was conducted using the method of serotonin-induced spasmogenic response of an isolated rat dam. The nvestigations were carried out using a buffer of De Jalognes with constant oxygenation and incubation at 24 ° C. The level of the anti-serotonin action was evaluated by eliminating the possibility of serotonin-induced spasm with the test substance at a concentration of 0.1 µmol. Registration of contractile response was carried out using the apparatus for isolated organs, isotonic transducer and recorder ("UnirecordUgoBasile", Italy). Statistic analysis was carried out using GraphPad Prism v. 5.0 program. Results. chlorinated and bromine derivatives of the molecule under study in a concentration of 0.1 µmol caused a decrease of spasmogenic effect of serotonin on the isolated rat dam. When studying the dose-dependent effect of serotonin in the presence of a compound we marked shift of the characteristic S-curve to the right. It corresponds to a standard curve of the reversible binding of ligands antagonists. The LogEC50 indicator of serotonin action in the presence of 0.1 µmol of HCl amounted to -6.0 ± 0.06, and for the hydrobromide -5.3 ± 0.14. Further research has shown a high stability of these compounds during a long-term storage in ambient conditions. Thus, compounds modified according to the principles of the pharmaceutical alternative retain their high anti-serotonin potential, but acquire the properties of greater stability. Conclusions: using the method of pharmaceutical alternatives we identified new compounds with higher chemical resistance. The findings about the equivalence of anti-serotonin effects of the compounds studied show their prospects for future research.