Synthesis and in vitro pharmacological evaluation of novel 2-hydroxypropyl-4-arylpiperazine derivatives as serotoninergic ligands

This paper reports the synthesis and the binding assays on the 5-HT1A, 5-HT2A and 5-HT2C receptors of new norbornene and exo-N-Hydroxy-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide derivatives in order to identify selective ligands for 5-HT1A subtype receptor. The combination of structural elements (heterocyclic nucleus, hydroxyl 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. The more active compounds were selected and further evaluated for their binding affinities on D1 , D2 dopaminergic and α1, α2 adrenergic receptors. The 4-[3-[4-(2-furoyl)piperazin-1-yl]propoxy-2-ol]-4-aza-tricyclo [5.2.1.02,6]dec-8-ene-3,5-dione (3e) with Ki = 5.04 nM, was the most active and selective derivative for the 5-HT2C receptor with respect to other serotonin receptors and the most selective derivative vs. dopaminergic and adrenergic receptor.