Dopaminergic agents for the treatment of cocaine abuse

Smith, Miles P.; Hoepping, Alexander; Johnson, Kenneth M.; Trzcińska, Monika; Kozikowski, Alan P.

doi:10.1016/s1359-6446(99)01332-x

Cited by 44 publications

(48 citation statements)

References 98 publications

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“…They identify an aromatic amino acid target for development of anticocaine medication. They support the idea that improved knowledge about cocaine selective target(s) in DAT could help the search for substrate-sparing anticocaine compounds acting selectively at DAT and/or at other monoamine transporters (Slusher et al, 1997;Smith et al, 1999).…”

supporting

confidence: 58%

Dopamine Transporter Mutants with Cocaine Resistance and Normal Dopamine Uptake Provide Targets for Cocaine Antagonism

Lin

Uhl

2002

Mol Pharmacol

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Cocaine's blockade of dopamine reuptake by brain dopamine transporters (DAT) is a central feature of current understanding of cocaine reward and addiction. Empirical screening of smallmolecule chemical libraries has thus far failed to provide successful cocaine blockers that allow dopamine reuptake in the presence of cocaine and provide cocaine "antagonism". We have approached this problem by assessing expression, dopamine uptake, and cocaine analog affinities of 56 DAT mutants in residues located in or near transmembrane domains likely to play significant roles in cocaine recognition and dopamine uptake. A phenylalanine-to-alanine mutant in putative DAT transmembrane domain 3, F154A, retains normal dopamine uptake, lowers cocaine affinity 10-fold, and reduces cocaine stereospecificity. Such mutants provide windows into DAT structures that could serve as targets for selective cocaine blockers and document how combined strategies of mutagenesis and small molecule screening may improve our abilities to identify and design compounds with such selective properties.The dopamine transporter (DAT) is a putative 12-transmembrane domain (TM) protein that takes up dopamine into neurons of brain pathways that contribute to behavioral reward (Ranaldi et al., 1999;Redgrave et al., 1999). Cocaine blockade of dopamine uptake by the DAT expressed by these neurons has been identified as a crucial component for cocaine reward, suggesting that selective blockade of cocaine recognition in this pathway could have therapeutic importance for development of anticocaine medication Villemagne et al., 1999).To improve understanding of the ways in which DAT recognizes cocaine and dopamine, hundreds of cocaine analogs have been synthesized and hundreds of DAT mutant and chimeric molecules constructed and characterized (Kitayama et al

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supporting

confidence: 58%

Dopamine Transporter Mutants with Cocaine Resistance and Normal Dopamine Uptake Provide Targets for Cocaine Antagonism

Lin

Uhl

2002

Mol Pharmacol

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“…However, the preponderance of patents and drugs developed for treating cocaine abuse and addiction belong to the dopaminergic class of agents, and are primarily indirect dopamine agonists (dopamine uptake inhibitors). 24 Reviews of these compounds as potential treatments for cocaine abuse that highlights the dopamine hypothesis as the basis for the development for these agents have appeared [25][26][27] recently. Analogues of cocaine, and particularly the 3-aryl tropane class of dopamine uptake inhibitors have received the widest attention.…”

Section: S E a R C H F O R A C O C A I N E A B U S E M E D I C A T mentioning

confidence: 99%

“…Highly potent and selective dopamine uptake inhibitors have been evaluated preclinically for their potential as cocaine-abuse medications. Although numerous classes of DAT ligands have been synthesized, 25 to date, the 3-aryl tropanes, based on cocaine, have been the most widely studied. In addition, highly potent and selective DAT inhibitors, based on GBR 12909, have been discovered.…”

Section: S U M M a R Y A N D F U T U R E D I R E C T I O N Smentioning

confidence: 99%

Probes for the dopamine transporter: New leads toward a cocaine‐abuse therapeutic—A focus on analogues of benztropine and rimcazole

Newman

Kulkarni

2002

Medicinal Research Reviews

107

144

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In an attempt to discover a cocaine-abuse pharmacotherapeutic, extensive investigation has been directed toward elucidating the molecular mechanisms underlying the reinforcing effects of this psychostimulant drug. The results of these studies have been consistent with the inhibition of dopamine uptake, at the dopamine transporter (DAT), which results in a rapid and excessive accumulation of extracellular dopamine in the synapse as being the mechanism primarily responsible for the locomotor stimulant actions of cocaine. Nevertheless, investigation of the serotonin (SERT) and norepinephrine (NET) transporters, as well as other receptor systems, with which cocaine either directly or indirectly interacts, has suggested that the DAT is not solely responsible for the reinforcing effects of cocaine. In an attempt to further elucidate the roles of these systems in the reinforcing effects of cocaine, selective molecular probes, in the form of drug molecules, have been designed, synthesized, and characterized. Many of these compounds bind potently and selectively to the DAT, block dopamine reuptake, and are behaviorally cocaine-like in animal models of psychostimulant abuse. However, there have been exceptions noted in several classes of dopamine uptake inhibitors that demonstrate behavioral profiles that are distinctive from cocaine. Structure-activity relationships between chemically diverse dopamine uptake inhibitors have suggested that different binding interactions, at the molecular level on the DAT, as well as divergent actions at the other monoamine transporters may be related to the differing pharmacological actions of these compounds, in vivo. These studies suggest that novel dopamine uptake inhibitors, which are structurally and pharmacologically distinct from cocaine, may be developed as potential cocaine-abuse therapeutics.

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“…14,[25][26][27] In contrast to the extensive structure-activity relationship (SAR) studies for DAT-selective ligands, fewer SAR studies have been focused on the discovery and development of ligands with a variety of transporter selectivity for both DAT and SERT. 14,[28][29][30][31] Novel ligands that differ in their transporter affinity and SERT:DAT ratio may help reveal the pharmacological mechanisms relevant to stimulant abuse, and also lead to an high efficacy medication for cocaine abuse, with few adverse reactions. Such a medication may also reduce the incidence of HIV infection.…”

Section: Graphical Abstract Introductionmentioning

confidence: 99%

Design and Synthesis of 2- and 3-Substituted-3-phenylpropyl Analogs of 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(Diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine: Role of Amino, Fluoro, Hydroxyl, Methoxyl, Methyl, Methylene, and Oxo Substituents on Affinity for the Dopamine and Serotonin Transporters

et al. 2008

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In our search for potential cocaine-abuse therapeutic agents, novel derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909, 1) and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935, 2) with various substituents in positions C2 and C3 of the phenylpropyl side chain were designed, synthesized and evaluated for their ability to bind to the dopamine transporter (DAT) and the serotonin transporter (SERT). The affinities of these ligands for DAT and SERT were controlled by the position of the substituents and their electronic and steric effects. This information could help us better understand and predict the influence of structural modification, and to discover new high-affinity DAT ligands possessing a range of affinities for SERT. The C2 series showed a quite different structure-activity relationship from the C3 series. In the C2 series, the substituent in the S configuration with a lone-pair of electrons significantly enhanced the affinity for DAT, whereas the steric effect of the substituent was detrimental to DAT binding affinity. In the C3 series, neither the lone electron pair nor the steric effect of the substituent seemed to affect DAT binding affinity, while sp 2 hybridized substituents had a detrimental effect on affinity for DAT. 2-Fluoro-substituted analogs (S)-10 and (R)-10 displayed substantial enantioselectivity in transporter affinity. In the Author Manuscript series, (S)-10 had the highest DAT binding affinity and good DAT selectivity. The 2-aminosubstituted (R)-8 showed the highest SERT binding affinity in this series and essentially the same affinity for DAT (K i = 22 and 20 nM, respectively). Thus, (R)-8 might be a lead for the discovery of a dual-action transporter ligand able to simultaneously block DAT and SERT. Compounds 16 and 18, the oxygenated derivatives of 2, possessed the best selectivity for DAT (SERT/DAT ratio = 254 and 250, respectively). HHS Public Access Graphical Abstract Introduction

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Dopaminergic agents for the treatment of cocaine abuse

Cited by 44 publications

References 98 publications

Dopamine Transporter Mutants with Cocaine Resistance and Normal Dopamine Uptake Provide Targets for Cocaine Antagonism

Dopamine Transporter Mutants with Cocaine Resistance and Normal Dopamine Uptake Provide Targets for Cocaine Antagonism

Probes for the dopamine transporter: New leads toward a cocaine‐abuse therapeutic—A focus on analogues of benztropine and rimcazole

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