Design and synthesis of 2-[4-[4-(m-(ethylsulfonamido)-phenyl)piperazin-1-yl]butyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazole (EF-7412) using neural networks. A selective derivative with mixed 5-HT1A/D-2 antagonist properties

A test series of 32 phenylpiperazines III with affinity for 5-HT1A and alph a(1) receptors was subjected to QSAR analysis using artificial neural netwo rks (ANNs), in order to get insight into the structural requirements that a re responsible for 5-HT1A/alpha(1) selectivity. Good models and predictive power were obtained for 5-HT1A and alpha(1) receptors. A comparison of thes e models gives information for the design of the new ligand EF-7412 (5-HT1A :K-i (nM)= 27; alpha(1):K-i (nM) > 1000). This derivative displayed affinit y for dopamine D-2 receptor (K-i=22 nM) and is selective for all other rece ptor examined (5-HT2A, 5-HT3, 5-HT3, 5-HT4 and Bz). EF-7412 acts an antagon ist in vivo in pre- and postsynaptic 5-MT1A receptor sites and as an antago nist in dopamine D-2 receptor. (C) 1999 Elsevier Science Ltd. All rights re served.