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/D2 antagonist properties

  • Bioorg Med Chem Lett. 1999 Jun 21;9(12):1679-82. doi: 10.1016/s0960-894x(99)00254-1.
M L López-Rodríguez  1 ,  M J Morcillo ,  E Fernández ,  M L Rosado ,  L Orensanz ,  M E Beneytez ,  J Manzanares ,  J A Fuentes ,  K J Schaper
Affiliations
  • 1. Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, Madrid, Spain. [email protected]
PMID: 10397500 DOI: 10.1016/s0960-894x(99)00254-1
Abstract

A test series of 32 phenylpiperazines III with affinity for 5-HT1A and alpha1 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-HT1A/alpha1 selectivity. Good models and predictive power were obtained for 5-HT1A and alpha1 receptors. A comparison of these models gives information for the design of the new ligand EF-7412 (5-HT1A:Ki(nM)= 27; alpha1: Ki(nM) > 1000). This derivative displayed affinity for dopamine D2 receptor (Ki = 22 nM) and is selective for all Other receptor examined (5-HT2A, 5-HT3, 5-HT4 and Bz). EF-7412 acts an antagonist in vivo in pre- and postsynaptic 5-HT1A receptor sites and as an antagonist in dopamine D2 receptor.

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