European Journal of Medicinal Chemistry 2012-01-01

New potent 5-HT(2A) receptor ligands containing an N'-cyanopicolinamidine nucleus: Synthesis and in vitro pharmacological evaluation.

Ferdinando Fiorino, Beatrice Severino, Elisa Magli, Elisa Perissutti, Francesco Frecentese, Antonella Esposito, Giuseppina Maria Incisivo, Antonio Ciano, Paola Massarelli, Cristina Nencini, Vincenzo Santagada, Giuseppe Caliendo

Index: Eur. J. Med. Chem. 47(1) , 520-9, (2012)

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Abstract

N'-cyanopicolinamidine derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to serotonin 5-HT(1A), 5-HT(2A) and 5-HT(2C) receptors were evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine) known to be critical for affinity to 5-HT(1A) receptors and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed affinity in nanomolar and subnanomolar range at 5-HT(2A) and moderate to no affinity for other relevant receptors (5-HT(1A), 5-HT(2C), D(1), D(2), α(1) and α(2)). N'-cyano-N-(3-(4-(3-chlorophenyl)piperazin-1-yl)propyl)-picolinamidine (4l) with K(i)=0.000185nM, was the most active and selective derivative for the 5-HT(2A) receptor compared to other serotoninergic, dopaminergic and adrenergic receptors.Copyright © 2011 Elsevier Masson SAS. All rights reserved.