Spiroxatrine derivatives towards 5-HT1A receptor selectivity
Research output: Contribution to journal › Journal article › Research › peer-review
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
Original language | English |
---|---|
Journal | Pharmacological Reports |
Volume | 72 |
Issue number | 2 |
Pages (from-to) | 427-434 |
Number of pages | 8 |
ISSN | 1734-1140 |
DOIs | |
Publication status | Published - 2020 |
- Spiroxatrine derivatives, 5-HT1A receptor, alpha(2)-Adrenoceptors, NOP ligands, SAR studies, MIGRAINE, AGONISTS, LIGANDS, POTENT, ORL1
Research areas
ID: 245322111