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Bioorg Med Chem Lett. 2010 May 1;20(9):2978-82. doi: 10.1016/j.bmcl.2010.02.106. Epub 2010 Mar 3.

New 5-HT(1A) receptor ligands containing a N'-cyanoisonicotinamidine nucleus: synthesis and in vitro pharmacological evaluation.

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Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli Federico II, Via D. Montesano, 49, 80131 Napoli, Italy.


N'-cyanoisonicotinamidine derivatives, linked to an arylpiperazine moiety, were prepared to identify highly selective and potent 5-HT(1A) 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-HT(1A) 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-HT(1A) and moderate to no affinity for other relevant receptors (5-HT(2A), 5-HT(2C), D(1), D(2), alpha(1) and alpha(2)). N'-cyano-N-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)isonicotinamidine (4o) with K(i)=0.038 nM, was the most active and selective derivative for the 5-HT(1A) receptor with respect to other serotoninergic, dopaminergic and adrenergic receptors.

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