The SF5 moiety as promising substituent for the design of novel D2 and D3 receptors ligands

Abstract

Dopamine receptors are divided into two subclasses: D1 like receptors (D1 and D5 subtypes) and D2 like receptors (D2, D3 and D4) [1]. Based on a general pharmacophore [2] we introduced the pentafluorosulfanyl moiety (SF5-) group as an interesting pharmacological tool to investigate D2 like receptors. This moiety displays high electronegativity and lipophilicity, while being thermally stable [3] and more resistant to hydrolysis in comparison to that of other polyfuorinated moieties (e.g. CF3 or OCF3). Four novel compounds with SF5 substituent have been synthesized, in silico and in vitro tested in order to examine their affinity and selectivity towards human dopamine D2 and D3 receptor subtypes. All compounds showed high affinity in the nanomolar concentration ranges at both receptors with ST 2200 expressing highest selectivity. In silico examination determined high values of coefficient of determination (R2) and Spearman correlation coefficient revealed good correlation between in silico parameters and experimentally obtained Ki values. These results show that pentafluorosulfanyl substituent is a highly suitable moiety for structural variations that has to be further investigated and could serve as novel substituent in numerous compound classes.