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 α2-AR (Adrenergic Receptors). Methods: Binding affinities were determined on cells expressing human cloned receptors for 5-HT1A/B/D and α2A/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 α2 subtypes, spanning from 5 to 7.5 pKi values. Moreover, they show affinity values in a μM–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 pKi value of 8.43 similar to spiroxatrine but, notably, it has a 5-HT1A favorable selectivity ratio of 52, 8 and 29, respectively over α2A, α2B and α2C 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: [Figure not available: see fulltext.]

Spiroxatrine derivatives towards 5-HT1A receptor selectivity / Sorbi, C.; Tait, A.; Battisti, U. M.; Brasili, L.. - In: PHARMACOLOGICAL REPORTS. - ISSN 1734-1140. - 72:2(2020), pp. 427-434. [10.1007/s43440-019-00039-4]

Spiroxatrine derivatives towards 5-HT1A receptor selectivity

Sorbi C.;Tait A.;Battisti U. M.;Brasili L.
2020

Abstract

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 α2-AR (Adrenergic Receptors). Methods: Binding affinities were determined on cells expressing human cloned receptors for 5-HT1A/B/D and α2A/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 α2 subtypes, spanning from 5 to 7.5 pKi values. Moreover, they show affinity values in a μM–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 pKi value of 8.43 similar to spiroxatrine but, notably, it has a 5-HT1A favorable selectivity ratio of 52, 8 and 29, respectively over α2A, α2B and α2C 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: [Figure not available: see fulltext.]
30-gen-2020
72
2
427
434
Spiroxatrine derivatives towards 5-HT1A receptor selectivity / Sorbi, C.; Tait, A.; Battisti, U. M.; Brasili, L.. - In: PHARMACOLOGICAL REPORTS. - ISSN 1734-1140. - 72:2(2020), pp. 427-434. [10.1007/s43440-019-00039-4]
Sorbi, C.; Tait, A.; Battisti, U. M.; Brasili, L.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1207343
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