Binding of Mazindol and Analogs to the Human Serotonin and Dopamine Transporters

Abstract

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.

Rigid Adenine Nucleoside Derivatives as Novel Modulators of the Human Sodium Symporters for Dopamine and Norepinephrine

“…The phenomenon of enhanced binding at the hDAT of radioligands that are derived from the structure of cocaine is unprecedented (for a review, see Reith et al, 2015). This phenomenon was observed using radiolabeled tropanes, which bind with high affinity to the DAT, NET, and SERT, and radiolabeled mazindol, which like the nucleoside analogs, binds to the hDAT and hNET with greater affinity than to the hSERT (Eshleman et al, 1999;Severinsen et al, 2014). At the same time, these rigid nucleosides inhibited DA uptake in a similar fashion to cocaine, suggesting an allosteric interaction with respect to the cocaine binding site.…”

“…Upon enlargement of the N 6 group in the 5-chlorothien-2-yl triazole series (compounds 29-31) weak binding inhibition was observed only with the largest group, i.e., N 6 -3-chlorobenzyl (compound 31). Six compounds (6, 7, 8, 9, 16, and 19) (Severinsen et al, 2014).…”

“…Mazindol [(6)-5-(4-chlorophenyl)-3,5-dihydro-2H-imidazo[2,1-a]isoindol-5-ol] is another ligand in a different structural class that binds to the DAT and other transporters and blocks neurotransmitter uptake (Severinsen et al, 2014).…”

Ligand Selectivity among the Dopamine and Serotonin Transporters Specified by the Forward Binding Reaction

“…The analysis of the interaction between the drugs and their targets has mostly relied on radioligand-binding experiments (Sarker et al, 2010;Andersen et al, 2011Andersen et al, , 2014Severinsen et al, 2014). For technical reasons, these approaches are limited to high-affinity ligands with slow off rates.…”

“…Some inhibit all three monoamine transporters, whereas others show exquisite selectivity . The basis for this selectivity has been explored by a combination of tools, including mutagenesis, docking, and molecular modeling studies (see, e.g., Andersen et al, 2011Andersen et al, , 2014Severinsen et al, 2014). However, the insights provided by these studies are limited since inhibitor binding has mostly been described by equilibrium parameters (e.g., K i or IC 50 ).…”