1A , 5HT 2A and 5HT 2C receptor ligands containing a picolinic nucleus: Synthesis, in vitro and in vivo pharmacological evaluation]]>

摘要

Graphical abstract Display Omitted Highlights ? Serotonin is involved in physiological and pathophysiological processes. ? Picolinamide 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, selectivity and functional activity at 5-HT 1A , 5-HT 2A and 5HT 2C receptors. Abstract Picolinamide derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to 5-HT 1A , 5-HT 2A and 5-HT 2C receptors was evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine), known to play critical roles in affinity for serotoninergic receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed high affinity in nanomolar and subnanomolar range at 5-HT 1A , 5-HT 2A and 5-HT 2C receptors and moderate or no affinity for other relevant receptors (D 1 , D 2 , α 1 and α 2 ). N-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)picolinamide ( 3o ) with Ki=0.046nM, was the most affine and selective derivative for the 5-HT 1A receptor compared to other serotoninergic dopaminergic and adrenergic receptors. N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)picolinamide ( 3b ), instead, showed a subnanomolar affinity towards 5-HT 2A with Ki=0.0224nM, whereas N-(2-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)ethyl)picolinamide ( 3s ) presented an attractive 5-HT 2C affinity with K i =0.8nM. Moreover, the compounds having better affinity and selectivity binding profiles towards 5-HT 2A were selected and tested on rat ileum, to determine their effect on 5HT induced contractions. Those more selective towards 5-HT 1A receptors were studied in vivo on several behavioral tests. ]]>