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, 1 and 2). 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-HT2A with 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.

New 5-HT1A, 5HT2Aand 5HT2Creceptor ligands containing a picolinic nucleus: Synthesis, in vitro and in vivo pharmacological evaluation / Fiorino, Ferdinando; Magli, Elisa; Kä dzierska, Ewa; Ciano, Antonio; Corvino, Angela; Severino, Beatrice; Perissutti, Elisa; Frecentese, Francesco; Di Vaio, Paola; Saccone, Irene; Izzo, Angelo A.; Capasso, Raffaele; Massarelli, Paola; Rossi, Ilaria; Orzelska-gã²rka, Jolanta; Kotliå ska, Jolanta Helena; Santagada, Vincenzo; Caliendo, Giuseppe. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 25:20(2017), pp. 5820-5837. [10.1016/j.bmc.2017.09.018]

New 5-HT1A, 5HT2Aand 5HT2Creceptor ligands containing a picolinic nucleus: Synthesis, in vitro and in vivo pharmacological evaluation

Fiorino, Ferdinando
;
Magli, Elisa;Ciano, Antonio;Corvino, Angela;Severino, Beatrice;Perissutti, Elisa;Frecentese, Francesco;Di Vaio, Paola;Saccone, Irene;Izzo, Angelo A.;Capasso, Raffaele;Santagada, Vincenzo;Caliendo, Giuseppe
2017

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, 1 and 2). 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-HT2A with 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.
2017
New 5-HT1A, 5HT2Aand 5HT2Creceptor ligands containing a picolinic nucleus: Synthesis, in vitro and in vivo pharmacological evaluation / Fiorino, Ferdinando; Magli, Elisa; Kä dzierska, Ewa; Ciano, Antonio; Corvino, Angela; Severino, Beatrice; Perissutti, Elisa; Frecentese, Francesco; Di Vaio, Paola; Saccone, Irene; Izzo, Angelo A.; Capasso, Raffaele; Massarelli, Paola; Rossi, Ilaria; Orzelska-gã²rka, Jolanta; Kotliå ska, Jolanta Helena; Santagada, Vincenzo; Caliendo, Giuseppe. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 25:20(2017), pp. 5820-5837. [10.1016/j.bmc.2017.09.018]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/692751
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