Binding of mazindol and analogs to the human serotonin and dopamine transporters.
Mazindol has been explored as a possible agent in cocaine addiction pharmacotherapy. The tetracyclic compound inhibits both the dopamine transporter and the serotonin transporter, and simple chemical modifications considerably alter target selectivity. Mazindol, therefore, is an attractive scaffold for both understanding the molecular determinants of serotonin/dopamine transporter selectivity and for the development of novel drug abuse treatments. Using molecular modeling and pharmacologic profiling of rationally chosen serotonin and dopamine transporter mutants with respect to a series of mazindol analogs has allowed us to determine the orientation of mazindol within the central binding site. We find that mazindol binds in the central substrate binding site, and that the transporter selectivity can be modulated through mutations of a few residues in the binding pocket. Mazindol is most likely to bind as the R-enantiomer. Tyrosines 95 and 175 in the human serotonin transporter and the corresponding phenylalanines 75 and 155 in the human dopamine transporter are the primary determinants of mazindol selectivity. Manipulating the interaction of substituents on the 7-position with the human serotonin transporter Tyr175 versus dopamine transporter Phe155 is found to be a strong tool in tuning the selectivity of mazindol analogs and may be used in future drug design of cocaine abuse pharmacotherapies.
Laboratory of Molecular Neurobiology, Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University Hospital, Risskov, Denmark (K.S., K.A.V.T., P.T.M., O.W., S.S.); and iNANO and inSPIN Centers (H.K., B.S.) and Department of Chemistry (C.S.-E., H.H.J.), Aarhus University, Aarhus, Denmark.
Kasper
K
Severinsen
Heidi
H
Koldsø
Katrine Almind Vinberg
KA
Thorup
Christina
C
Schjøth-Eskesen
Pernille Thornild
PT
Møller
Ove
O
Wiborg
Henrik Helligsø
HH
Jensen
Steffen
S
Sinning
Birgit
B
Schiøtt
D001665:Binding Sites; D002478:Cells, Cultured; D019970:Cocaine-Related Disorders / Q000188:drug therapy; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D006801:Humans; D008454:Mazindol / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D008958:Models, Molecular; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship
D050483:Dopamine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D008454:Mazindol