New potent 5-HT2A receptor ligands containing an N′-cyanopicolinamidine nucleus: Synthesis and in vitro pharmacological evaluation

N′-cyanopicolinamidine derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to serotonin 5-HT1A, 5-HT2A and 5-HT2C receptors were evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine) known to be critical for affinity to 5-HT1A 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-HT2A and moderate to no affinity for other relevant receptors (5-HT1A, 5-HT2C, D1, D2, α1 and α2). N′-cyano-N-(3-(4-(3-chlorophenyl)piperazin-1-yl)propyl)-picolinamidine (4l) with Ki = 0.000185 nM, was the most active and selective derivative for the 5-HT2A receptor compared to other serotoninergic, dopaminergic and adrenergic receptors.

N′-cyanopicolinamidine derivatives were prepared to obtain a structure-affinity/selectivity relationship study between N′-cyanoisonicotinamidine and the precedently synthesized N′-cyanopicolinamidine derivatives. N-(3-(4-(3-chlorophenyl)piperazin-1-yl)propyl)-N′-cyanopicolinamidine (4lKi = 0.000185 nM) was the most active 5-HT2A ligand.Figure optionsDownload as PowerPoint slideHighlights
► Serotonin is involved in physiological and pathophysiological processes.
► N′-cyanopicolinamidine derivatives, linked to an arylpiperazine moiety.
► The combination of structural elements known to be critical for affinity to serotoninergic receptors.
► In binding studies, several molecules showed high affinity and selectivity at 5-HT2A.