Spiroxatrine derivatives towards 5-HT_1A receptor selectivity

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-HT₁ receptor subtypes and with respect to α₂-AR (Adrenergic Receptors).

Binding affinities were determined on cells expressing human cloned receptors for 5-HT_1A/B/D and α_2A/B/C subtypes. The Ki values were determined for those with at least 50% radioligand inhibition.

All our derivatives show a moderate affinity for α₂ subtypes, spanning from 5 to 7.5 pK_i values. Moreover, they show affinity values in a μM-nM range at the 5-HT_1A receptor, while they are practically inactive at 5-HT_1B and 5-HT_1D subtypes. Compound 11, the best of the series, has a 5-HT_1A pK_i value of 8.43 similar to spiroxatrine but, notably, it has a 5-HT_1A favorable selectivity ratio of 52, 8 and 29, respectively over α_2A, α_2B and α_2C adrenoceptor subtypes.

In this SAR study, a 5-HT_1A 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.