Synthesis, docking studies, and pharmacological evaluation of 2‐hydroxypropyl‐4‐arylpiperazine derivatives as serotoninergic ligands. Issue 5 (5th February 2021)

• Record Type: Journal Article
• Authors: Magli, Elisa; Kędzierska, Ewa; Kaczor, Agnieszka A.; Bielenica, Anna; Severino, Beatrice; Gibuła‐Tarłowska, Ewa; Kotlińska, Jolanta H.; Corvino, Angela; Sparaco, Rosa; Esposito, Giovanna; Albrizio, Stefania; Perissutti, Elisa; Frecentese, Francesco; Leśniak, Anna; Bujalska‐Zadrożny, Magdalena; Struga, Marta; Capasso, Raffaele; Santagada, Vincenzo; Caliendo, Giuseppe; Fiorino, Ferdinando
• Is Part Of: Archiv der Pharmazie. Volume 354:Issue 5(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-02-05
• Subjects: 5‐HT1A receptor ligands -- arylpiperazine derivatives -- exo‐N‐hydroxy‐7‐oxabicyclo[2.2.1]hept‐5‐ene‐2, 3‐dicarboximide -- norbornene nucleus -- serotonin; Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.202000414
• Languages: English
• ISSNs: 0365-6233

Abstract

Abstract: A new series of norbornene and exo ‐ N ‐hydroxy‐7‐oxabicyclo[2.2.1]hept‐5‐ene‐2, 3‐dicarboximide derivatives was prepared, and their affinities to the 5‐HT1A, 5‐HT2A, and 5‐HT2C receptors were evaluated and compared with a previously synthesized series of derivatives characterized by the same nuclei, to identify selective ligands for the subtype receptors. Arylpiperazines represent one of the most important classes of 5‐HT1A R ligands, and the research of new derivatives has been focused on the modification of one or more portions of this pharmacophore. The combination of structural elements (heterocyclic nucleus, hydroxyalkyl chain, and 4‐substituted piperazine), known to be critical for the affinity to 5‐HT1A receptors, and the proper selection of substituents resulted in compounds with high specificity and affinity toward serotoninergic receptors. The most active compounds were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that 3e, 4j, and 4n were the most active and promising derivatives for the serotonin receptor considered in this study. Abstract : Several norbornene and exo ‐ N ‐hydroxy‐7‐oxabicyclo[2.2.1]hept‐5‐ene‐2, 3‐dicarboximide derivatives with affinity toward 5‐HT1A, 5‐HT2A, and 5‐HT2C receptors are described in this study. Among these, the compound containing a naphthylpiperazine moiety (4n ) showed an interesting antagonist profile at the 5‐HT1A receptor.