New 5-HT1A, 5HT2A and 5HT2C receptor ligands containing a picolinic nucleus: Synthesis, in vitro and in vivo pharmacological evaluation. Issue 20 (15th October 2017)

• Record Type: Journal Article
• Authors: Fiorino, Ferdinando; Magli, Elisa; Kędzierska, 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-Gòrka, Jolanta; Kotlińska, Jolanta Helena; Santagada, Vincenzo; Caliendo, Giuseppe
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 20(2017)
• Page Start: 5820
• Page End: 5837
• Publication Date: 2017-10-15
• Subjects: Picolinamide derivatives -- Synthesis -- 5-HT1A, 5-HT2A and 5-HT2C ligands -- Binding assays, in vitro assay -- Behavioural tests; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.09.018
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Serotonin is involved in physiological and pathophysiological processes. Picolinamide derivatives, linked to an arylpiperazine moiety. The combination of structural elements known to be critical for affinity to serotoninergic receptors. In binding studies, several molecules showed high affinity, selectivity and functional activity at 5-HT1A, 5-HT2A and 5HT2C receptors. 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, α1 and α2 ). 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.