Mazindol Analogues as Potential Inhibitors of the Cocaine Binding Site at the Dopamine Transporter

Houlihan, William J.; Kelly, Lawrence A.; Pankuch, Jessica; Koletar, Judith; Brand, Leonard; Janowsky, and Aaron; Kopajtic, Theresa

doi:10.1021/jm010302r

Cited by 28 publications

(31 citation statements)

References 51 publications

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“…PaMLAC provides a complementary method in which a battery of mazindol analogs and complementary protein mutants allows us to extensively investigate the position of specific ligand-protein interaction points. In this study, we used racemic analogs previously described by Houlihan et al (2002) with four novel mazindol analogs (49 substituent analogs 5-8). Compound 5 was furthermore crystallized and the structure was solved by crystallography (see the Supplemental Experimental Procedures).…”

Section: Resultsmentioning

confidence: 99%

“…Mazindol is selective toward hDAT over hSERT and has been used as a starting molecule in the synthesis of different functionalized analogs by Houlihan et al (2002). Novel analogs were synthesized and tested in this study (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…1) for hSERT and hDAT mutants were explored. Of the original mazindol analogs from Houlihan et al (2002), three have a significant preference for wild-type hDAT over wild-type hSERT; compounds 1, 2, and 3 show a more than 100-fold preference for hDAT, whereas analog 4 only shows 36-fold selectivity. The novel analogs reported here were chosen to aid experimental validation of the mazindol binding mode and they generally show lower potency; however, two analogs show increased selectivity for hSERT.…”

Section: Introductionmentioning

confidence: 99%

“…The two enantiomers of mazindol and its analogs exist in a dynamic equilibrium between three isomers (the keto and the R and S-ol forms, respectively) with the R or S-ol being the only relevant forms at physiologic pH (Houlihan et al, 2002). These two enantiomers may have markedly different protein binding affinities, which cannot easily be measured experimentally due their presumed easy interconversion.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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“…For example, physostigmine, a centrally acting cholinesterase inhibitor, was shown to decrease manic symptoms and increase depressed reaction [65] . Later on, many studies provided information that largely supported the hypothesis [64,66,67] .…”

Section: Acetylcholine (Ach) -Anticipation Markermentioning

confidence: 95%

Differentiation of Primary Emotions through Neuromodulators: Review of Literature

Wang

Yuan

et al. 2015

International Journal of Neurology Research

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Emotional mental disorders are a leading cause of disabilities worldwide. Despite the obvious importance of emotion for human existence, controversy still abounds over the definition of emotion, the number of emotions that exit, whether different emotions have different physiological signatures. In this paper, we review papers about the emotional functions of neuromodulators: dopamine (DA), norepinephrine (NE), serotonin (5-HT) and acetyl choline (ACh), and propose that they act as the primary neural basis for 5 primary emotions (joy, anger/fear, sadness and missing). DA is a rewarding signal for salient stimuli such as food, sex and other needs. 5-HT has been related to depression for decades, it might be a marker for dislike/disgusting things. NE is the substrate for surprise, whose release induces "fight or flight" behaviors, or fear and anger emotions. Even though anger and fear are common emotions, there are no previous papers differentiating them or probing into their relationships. Here we found that fear and anger usually come hand in hand with fear followed by anger. And we give an equation to describe their relationships: The total amount of Surprise/stress = fear + anger. This equation fits in both duration and tension. Finally we introduced ACh emotions, which are opposite to NE induced stressful emotions. These emotions include "missing and wanting", "calm/tame", affectionate, submissive, et al. The significance of ACh emotions lies in the treatment for aggressive, impulsive behaviors, or phobia and manic disorders. In all, there might be 5 basic emotions (joy, anger/fear, sadness and missing).

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Monoamine reuptake inhibitors: highlights of recent research developments

Walter

2005

Drug Development Research

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Monoamine reuptake inhibitors are in clinical use for the treatment of major psychiatric disorders. Selective serotonin reuptake inhibitors are widely used in the treatment of depression. Selective norepinephrine reuptake inhibitors are used in the treatment of ADHD and depression. Compounds that enhance multiple monoamines appear to have synergistic effects and have been used for various indications. This review presents highlights from the literature on monoamine reuptake inhibitors published between 2000 and July 2005. It focuses on novel structure-activity relationship studies in established classes of monoamine reuptake inhibitors and structurally novel types. Drug Dev. Res. 65:97-118, 2005.

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Mazindol Analogues as Potential Inhibitors of the Cocaine Binding Site at the Dopamine Transporter

Cited by 28 publications

References 51 publications

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

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

Differentiation of Primary Emotions through Neuromodulators: Review of Literature

Monoamine reuptake inhibitors: highlights of recent research developments

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