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Title: Searching for serotonin 5-HT7 receptor antagonists among 5,5-disubstituted hydantoin derivatives


Design, synthesis and biological evaluation of novel serotonin 5-HT7R ligands and computer-aided SAR analysis, based on obtained results, were the main aim of this PhD dissertation.Compound MF-8, the first highly active and selective 5-HT7R agent found in the Department of Technology and Biotechnology of Drugs, was selected as a lead structure. Three series of novel compounds (45 final products) have been synthesized via three step chemical pathway as well as 4 optically pure stereoisomers of the lead were obtained. More than 30% of novel derivatives showed very high affinity towards the 5-HT7R (Ki < 20 nM), including 12 ones with Ki <10 nM. Additionally, majority of the compounds turned out to be selective, but less than lead MF-8. An exception was, with the highest selectivity over 5-HT1AR among the whole investigated library of hydantoins (series A-C and previously tested phenytoin derivatives). The computer-aided SAR analysis led to identification of structural fragments necessary to trigger 5-HT7R affinity among this chemical class.The performed in vivo behavioral tests, for four the most active hydantoin compounds and the most selective one (KKB16), confirmed their antidepressant activity. Interestingly, the compound with the highest metabolic stability and selectivity (KKB16), instead of the most potent 5-HT7 agents, displayed the most significant action in vivo.

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Level of degree:

2 - studia doktoranckie

Degree discipline:

farmacja ; psychiatria

Degree grantor:

Wydział Farmaceutyczny


Handzlik, Jadwiga ; Kurczab, Rafał

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pol; eng

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tylko w bibliotece

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Last modified:

Mar 13, 2023

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Oct 13, 2020

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ZB-129269 Mar 13, 2023


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