QSAR study and synthesis of new phenyltropanes as ligands of the dopamine transporter (DAT)

Sylvie Mavel (1) , Zoya Mincheva , Nathalie Méheux , Yvan Carcenac (2) , Denis Guilloteau (3) , Mohamed Abarbri (4) , Patrick Emond (3)

1 Equipe neurogénétique et neurométabolomique
2 ILV - Institut Lavoisier de Versailles
3 iBrain - Inserm U1253 - UNIV Tours - Imagerie et cerveau
4 UMR ISP - Infectiologie et Santé Publique

The dopamine transporter (DAT) plays a pivotal role in the regulation of dopamine neurotransmission, and is involved in a number of physiological functions and brain disorders. Furthermore the DAT analysis by molecular imaging techniques is a useful tool for the diagnosis and follow up treatment of diseases involving the DAT. In order to predict the affinity of new derivatives for the DAT, different QSAR molecular modeling models based on cocaine were compared. We have evaluated in these models tropane derivatives synthesized with original synthons which coupled properties of both fluorine and iodine atoms. One compound showed a high in vitro affinity and selectivity for the DAT (K-i = 0.87 +/- 0.04 nM). This compound should be radiolabeled with radioiodine for further investigations by SPECT. (C) 2012 Elsevier Ltd. All rights reserved.

Keywords: Iodine; MOLECULAR-FIELD ANALYSIS; PARKINSONS-DISEASE; PHARMACOLOGICAL CHARACTERIZATION; GENETIC ALGORITHM; IMAGING AGENT; HIGH-AFFINITY; ANALOGS

Keywords: Dopamine transporter; 3D-QSAR; Tropane; SEROTONIN TRANSPORTER; COCAINE; SYSTEM

Domains: Chemical Sciences; Medicinal Chemistry

Sylvie Mavel, Zoya Mincheva, Nathalie Méheux, Yvan Carcenac, Denis Guilloteau, et al.. QSAR study and synthesis of new phenyltropanes as ligands of the dopamine transporter (DAT). Bioorganic and Medicinal Chemistry, 2012, 20 (4), pp.1388 - 1395. ⟨10.1016/j.bmc.2012.01.014⟩. ⟨hal-01826407⟩