Synthesis, docking studies, and pharmacological evaluation of 5HT2C ligands containing the N′‐cyanoisonicotinamidine or N′‐cyanopicolinamidine nucleus. Issue 5 (26th April 2019)

• Record Type: Journal Article
• Authors: Magli, Elisa; Kędzierska, Ewa; Kaczor, Agnieszka A.; Severino, Beatrice; Corvino, Angela; Perissutti, Elisa; Frecentese, Francesco; Saccone, Irene; Massarelli, Paola; Gibuła‐Tarłowska, Ewa; Kotlińska, Jolanta H.; Santagada, Vincenzo; Caliendo, Giuseppe; Fiorino, Ferdinando
• Is Part Of: Archiv der Pharmazie. Volume 352:Issue 5(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-04-26
• Subjects: 5‐HT1A, 5‐HT2A, and 5‐HT2C ligands -- arylpiperazine derivatives -- behavioral tests -- binding assays, in vitro assay; Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.201800373
• Languages: English
• ISSNs: 0365-6233

Abstract

Abstract: N ′‐Cyanoisonicotinamidine and N ′‐cyanopicolinamidine derivatives, linked to an arylpiperazine moiety, were prepared and their affinities to the 5‐HT1A, 5‐HT2A, and 5‐HT2C receptors were evaluated. Several of the newly synthesized compounds, tested by binding studies, showed nanomolar affinity at the 5‐HT1A and 5‐HT2C receptors and moderate or no affinity for other relevant receptors (D1, D2, α1, and α2 ). Compound8e ( K i = 21.4 nM) was the most affine for the 5‐HT2C receptor, showing, at the same time, a high selectivity with respect to the other receptors analyzed. Compounds4a and4c, instead, showed an interesting mixed 5‐HT1A /5‐HT2C activity with K i values of 21.3/11.5 and 23.2/6.48 nM, respectively. The compounds with better affinity and selectivity binding profiles toward 5‐HT2C (4a, 4c, 8b, and8e ) 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 compounds4a, 8b, and8e exerted antidepressant‐like effects and4a and8e revealed also significant anxiolytic properties. Among the developed derivatives, the most promising compound seems to be4a, which displayed antipsychotic‐, antidepressant‐ and anxiolytic‐like properties. No side effects, like catalepsy, motor‐impairment or ethanol‐potentiating effects, were observed after the injection of the tested compounds. Abstract : Several N ′‐cyanoisonicotinamidine and N ′‐cyanopicolinamidine derivatives with nanomolar affinity toward 5HT2C are described. Compound8e was the most affine for the 5‐HT2C receptor and showed anxiolytic and antidepressant activity in functional in vivo studies. Molecular docking studies supported the biological results.