Spiroxatrine derivatives towards 5-HT 1A receptor selectivity

• Published in: Pharmacological reports Vol. 72; no. 2; p. 427
• Main Authors: Sorbi, Claudia, Tait, Annalisa, Battisti, Umberto M, Brasili, Livio
• Format: Journal Article
• Language: English
• Published: Switzerland 01.04.2020
• Subjects: SAR studies; NOP ligands; Spiroxatrine derivatives; α2-Adrenoceptors; 5-HT1A receptor
• ISSN: 1734-1140

In our previous work, spiroxatrine was taken as reference compound to develop selective NOP ligands. Therefore, several triazaspirodecanone derivatives were synthesized. Here, we verify their selectivity towards other 5-HT receptor subtypes and with respect to α -AR (Adrenergic Receptors). Binding affinities were determined on cells expressing human cloned receptors for 5-HT and α subtypes. The Ki values were determined for those with at least 50% radioligand inhibition. All our derivatives show a moderate affinity for α subtypes, spanning from 5 to 7.5 pK  values. Moreover, they show affinity values in a μM-nM range at the 5-HT receptor, while they are practically inactive at 5-HT and 5-HT subtypes. Compound 11, the best of the series, has a 5-HT pK value of 8.43 similar to spiroxatrine but, notably, it has a 5-HT favorable selectivity ratio of 52, 8 and 29, respectively over α , α and α adrenoceptor subtypes. In this SAR study, a 5-HT selective ligand has been identified in which a tetralone moiety replaced the 1,4-benzodioxane of spiroxatrine and the methylene linker to the triazaspirodecanone portion was maintained in position 2.