33156-84-2Relevant academic research and scientific papers
Binding of mazindol and analogs to the human serotonin and dopamine transporterss
Severinsen, Kasper,Koldso, Heidi,Thorup, Katrine Almind Vinberg,Schjoth-Eskesen, Christina,Moller, Pernille Thornild,Wiborg, Ove,Jensen, Henrik Helligso,Sinning, Steffen,Schiott, Birgit
supporting information, p. 208 - 217 (2014/01/23)
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. Usingmolecularmodeling 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. Copyright
Mazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter
Houlihan, William J.,Kelly, Lawrence,Pankuch, Jessica,Koletar, Judith,Brand, Leonard,Janowsky, Aaron,Kopajtic, Theresa A.
, p. 4097 - 4109 (2007/10/03)
A series of mazindol (2) and homomazindol (3) analogues with a variety of electron-donating and electron-withdrawing groups in the pendant aryl group and the benzo ring C, as well as H, methoxy, and alkyl groups replacing the hydroxyl group were synthesized, and their binding affinities at the dopamine transporter (DAT) on rat or guinea pig striatal membranes were determined. Several active analogues were also evaluated for their ability to block uptake of DA, 5-HT, and NE and inhibit binding of [125I] RTI-55 at HEK-hDAT, HEK-hSERT, and HEK-hNET cells. Mazindane (26) was found to be a pro-drug, oxidizing (5-H → 5-OH) to mazindol on rat striatal membranes and HEK-hDAT cells. The 4′,7,8-trichloro analogue (38) of mazindol was the most potent and selective ligand for HEK-hDAT cells (DAT Ki = 1.1 nM; SERT/DAT = 1283 and NET/DAT = 38). Experimental results strongly favor the cyclic or ol tautomers of 2 and 3 to bind more tightly at the DAT than the corresponding keto tautomers.
2,3-Dihydro-5-alkoxy-5-phenyl-5H-imidazo[2,1-a]isoindoles
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, (2008/06/13)
Novel 2[2-(1,3-diazacycloalk-2-enyl)]benzophenone compounds and novel 1,3-diazacycloalkenyl[2,1-a]isoindole compounds having useful analgesic and psychostimulant properties are prepared inter alia by condensation of o-benzoylbenzaldehydes with aliphatic diamines.
