Design and synthesis of 2-[4-[4-(m-(ethylsulfonamido)-phenyl)piperazin- 1-yl]butyl]-1,3-dioxoperhydropyrrolo[1,2c]imidazole (EF-7412) using neural networks. A selective derivative with mixed 5-HT(1A)/D2 antagonist properties

Article abstract of DOI:10.1016/S0960-894X(99)00254-1

A test series of 32 phenylpiporazines III with affinity for 5-HT(1A) and α₁ receptors was subjected to QSAR analysis using artificial neural networks (ANNs), in order to get insight into the structural requirements that are responsible for 5-HT(1A)/α₁ selectivity. Good models and predictive power were obtained for 5-HT(1A) and α₁ receptors. A comparison of these models gives information for the design of the new ligand EF-7412 (5-HT(1A):K(i) (nM)= 27; α₁ (nM) > 1000). This derivative displayed affinity for dopamine D₂ receptor (K(i)= 22 nM) and is selective for all other receptor examined (5-HT(2A), 5-HT₃, 5-HT₄ and Bz). EF-7412 acts an antagonist in vivo in pre-and postsynaptic 5-HT(1A) receptor sites and as an antagonist in dopamine D₂ receptor.