Background 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 alpha(2)-AR (Adrenergic Receptors).

Methods Binding affinities were determined on cells expressing human cloned receptors for 5-HT1A/B/D and alpha(2A/B/C) subtypes. The Ki values were determined for those with at least 50% radioligand inhibition.

Results All our derivatives show a moderate affinity for alpha(2) subtypes, spanning from 5 to 7.5 pK(i) values. Moreover, they show affinity values in a mu M-nM range at the 5-HT1A receptor, while they are practically inactive at 5-HT1B and 5-HT1D subtypes. Compound 11, the best of the series, has a 5-HT1A pK(i) value of 8.43 similar to spiroxatrine but, notably, it has a 5-HT1A favorable selectivity ratio of 52, 8 and 29, respectively over alpha(2A), alpha(2B) and alpha(2C) adrenoceptor subtypes.

Conclusions In this SAR study, a 5-HT1A 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. Graphic abstract