Synthesis, in vitro and in vivo pharmacological evaluation of serotoninergic ligands containing an isonicotinic nucleus

Eur J Med Chem. 2016 Mar 3;110:133-50. doi: 10.1016/j.ejmech.2016.01.021. Epub 2016 Jan 18.


Isonicotinamide derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to 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 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-HT1A, 5-HT2A and 5-HT2C receptors and moderate or no affinity for other relevant receptors (D1, D2, α1 and α2). N-(3-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)propyl)isonicotinamide (4s) with Ki = 0.130 nM, was the most active and selective derivative for the 5-HT1A receptor compared to other serotoninergic, dopaminergic and adrenergic receptors. Compound 4o, instead, showed 5-HT2A affinity values in subnamolar range. Moreover, the compounds having better affinity and selectivity binding profile towards 5-HT1A and 5-HT2A receptors were selected in order to be tested by in vitro and in vivo assays to determine their functional activity.

Keywords: 5-HT(1A); 5-HT(2A) and 5-HT(2C) ligands; Behavioural tests; Binding assays; In vitro assay; Isonicotinamide derivatives.

MeSH terms

  • Animals
  • Body Temperature / drug effects
  • Humans
  • Ligands
  • Locomotion / drug effects
  • Male
  • Mice
  • Niacinamide / chemical synthesis
  • Niacinamide / chemistry*
  • Niacinamide / pharmacology*
  • Piperazine
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Receptor, Serotonin, 5-HT2A / metabolism*


  • Ligands
  • Piperazines
  • Receptor, Serotonin, 5-HT2A
  • Receptor, Serotonin, 5-HT1A
  • Piperazine
  • Niacinamide
  • isonicotinamide