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

M L López-Rodríguez; M J Morcillo; E Fernández; M L Rosado; L Orensanz; M E Beneytez; J Manzanares; J A Fuentes; K J Schaper

doi:10.1016/s0960-894x(99)00254-1

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.

Authors

M L López-Rodríguez¹, M J Morcillo, E Fernández, M L Rosado, L Orensanz, M E Beneytez, J Manzanares, J A Fuentes, K J Schaper

Affiliation

¹ Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, Madrid, Spain. mluzlr@eucmax.sim.ucm.es

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adrenergic alpha-1 Receptor Antagonists
Dopamine Antagonists / chemical synthesis
Dopamine Antagonists / chemistry
Dopamine Antagonists / pharmacology
Dopamine D2 Receptor Antagonists*
Drug Design
Neural Networks, Computer
Piperazines / chemical synthesis*
Piperazines / chemistry
Piperazines / pharmacology
Receptors, Dopamine D2 / metabolism
Receptors, Serotonin / drug effects*
Receptors, Serotonin / metabolism
Receptors, Serotonin, 5-HT1
Serotonin Antagonists / chemical synthesis*
Serotonin Antagonists / chemistry
Serotonin Antagonists / pharmacology*
Sulfonamides / chemical synthesis*
Sulfonamides / chemistry
Sulfonamides / pharmacology

Substances

Adrenergic alpha-1 Receptor Antagonists
Dopamine Antagonists
Dopamine D2 Receptor Antagonists
Piperazines
Receptors, Dopamine D2
Receptors, Serotonin
Receptors, Serotonin, 5-HT1
Serotonin Antagonists
Sulfonamides
EF 7412