Picolinamide derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to 5-HT1A, 5-HT2A and 5-HT2C receptors was evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine), known to play critical roles in affinity for serotoninergic receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed high affinity in nanomolar and subnanomolar range at 5-HT1A, 5-HT2A and 5-HT2C receptors and moderate or no affinity for other relevant receptors (D1, D2, alpha1and alpha2). N-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)picolinamide (3o) with Ki = 0.046 nM, was the most affine and selective derivative for the 5-HT1A receptor compared to other serotoninergic dopaminergic and adrenergic receptors. N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)picolinamide (3b), instead, showed a subnanomolar affinity towards 5-HT2Abwith Ki = 0.0224 nM, whereas N-(2-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)ethyl)picolinamide (3s) presented an attractive 5-HT2C affinity with Ki= 0.8 nM. Moreover, the compounds having better affinity and selectivity binding profiles towards 5-HT2A were selected and tested on rat ileum, to determine their effect on 5HT induced contractions. Those more selective towards 5-HT1A receptors were studied in vivo on several behavioral tests.
Fiorino, F., Magli, E., Kȩdzierska, E., Ciano, A., Corvino, A., Severino, B., et al. (2017). New 5-HT1A, 5HT2Aand 5HT2C receptor ligands containing a picolinic nucleus: Synthesis, in vitro and in vivo pharmacological evaluation. BIOORGANIC & MEDICINAL CHEMISTRY, 25(20), 5820-5837 [10.1016/j.bmc.2017.09.018].
New 5-HT1A, 5HT2Aand 5HT2C receptor ligands containing a picolinic nucleus: Synthesis, in vitro and in vivo pharmacological evaluation
Massarelli, PaolaMethodology
;Rossi, IlariaMethodology
;
2017-01-01
Abstract
Picolinamide derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to 5-HT1A, 5-HT2A and 5-HT2C receptors was evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine), known to play critical roles in affinity for serotoninergic receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed high affinity in nanomolar and subnanomolar range at 5-HT1A, 5-HT2A and 5-HT2C receptors and moderate or no affinity for other relevant receptors (D1, D2, alpha1and alpha2). N-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)picolinamide (3o) with Ki = 0.046 nM, was the most affine and selective derivative for the 5-HT1A receptor compared to other serotoninergic dopaminergic and adrenergic receptors. N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)picolinamide (3b), instead, showed a subnanomolar affinity towards 5-HT2Abwith Ki = 0.0224 nM, whereas N-(2-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)ethyl)picolinamide (3s) presented an attractive 5-HT2C affinity with Ki= 0.8 nM. Moreover, the compounds having better affinity and selectivity binding profiles towards 5-HT2A were selected and tested on rat ileum, to determine their effect on 5HT induced contractions. Those more selective towards 5-HT1A receptors were studied in vivo on several behavioral tests.File | Dimensione | Formato | |
---|---|---|---|
Bioorg.Med.Chem. 2017, 25, 5820-5837.pdf
non disponibili
Descrizione: Articolo completo
Tipologia:
PDF editoriale
Licenza:
NON PUBBLICO - Accesso privato/ristretto
Dimensione
4.07 MB
Formato
Adobe PDF
|
4.07 MB | Adobe PDF | Visualizza/Apri Richiedi una copia |
MASSARELLI-New 5-HT1A-Post--Print.pdf
accesso aperto
Descrizione: Accepted Manuscript
Tipologia:
Post-print
Licenza:
Creative commons
Dimensione
955.49 kB
Formato
Adobe PDF
|
955.49 kB | Adobe PDF | Visualizza/Apri |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
https://hdl.handle.net/11365/1051259