New 5-HT1A receptor ligands containing a N′-cyanoisonicotinamidine nucleus: Synthesis and in vitro pharmacological evaluation |
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Authors: | Ferdinando Fiorino Beatrice Severino Francesca De Angelis Elisa Perissutti Elisa Magli Francesco Frecentese Antonella Esposito Paola Massarelli Cristina Nencini Vincenzo Santagada Giuseppe Caliendo |
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Institution: | 1. Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli ‘Federico II’, Via D. Montesano, 49, 80131 Napoli, Italy;2. Dipartimento di Farmacologia ‘G. Segre’ Università di Siena, Via delle Scotte, 6, 53100 Siena, Italy |
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Abstract: | N′-Cyanoisonicotinamidine derivatives, linked to an arylpiperazine moiety, were prepared to identify highly selective and potent 5-HT1A ligands as potential pharmacological tools in studies of wide spread psychiatric disorders. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine) known to be critical in order to have affinity on 5-HT1A receptor 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-HT1A and moderate to no affinity for other relevant receptors (5-HT2A, 5-HT2C, D1, D2, α1 and α2). N′-Cyano-N-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)isonicotinamidine (4o) with Ki = 0.038 nM, was the most active and selective derivative for the 5-HT1A receptor with respect to other serotoninergic, dopaminergic and adrenergic receptors. |
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