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.
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.
Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, Madrid, Spain. mluzlr@eucmax.sim.ucm.es
M L
ML
López-Rodríguez
M J
MJ
Morcillo
E
E
Fernández
M L
ML
Rosado
L
L
Orensanz
M E
ME
Beneytez
J
J
Manzanares
J A
JA
Fuentes
K J
KJ
Schaper
D058668:Adrenergic alpha-1 Receptor Antagonists; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D015195:Drug Design; D016571:Neural Networks, Computer; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D058668:Adrenergic alpha-1 Receptor Antagonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D010879:Piperazines; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D013449:Sulfonamides; C120936:EF 7412