QSAR study and synthesis of new phenyltropanes as ligands of the dopamine transporter (DAT).
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.
Université François-Rabelais, INSERM U930, CNRS ERL3106, 31 Avenue Monge, 37200 Tours, France. sylvie.mavel@univ-tours.fr
Sylvie
S
Mavel
Zoya
Z
Mincheva
Nathalie
N
Méheux
Yvan
Y
Carcenac
Denis
D
Guilloteau
Mohamed
M
Abarbri
Patrick
P
Emond
D003042:Cocaine / Q000737:chemistry / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis* / Q000494:pharmacology
D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D010636:Phenols; D014326:Tropanes; D003042:Cocaine