Heteroaromatic Analogs of 1-[2-(Diphenylmethoxy)ethyl]- and 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as High-Affinity Dopamine Reuptake Inhibitors

Matecka, Dorota; Lewis, David B.; Rothman, Richard B.; Dersch, Chris; Wojnicki, F.H.E.; Glowa, John R.; DeVries, A. Courtney; Pert, Agu; Rice, Kenner C.

doi:10.1021/jm9606599

Cited by 59 publications

(48 citation statements)

References 35 publications

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“…129 Although, self administration of GBR 12909 differed from cocaine in both rate and effective dose, suggesting differences in pharmacokinetics between these drugs. 129,130 Suppression of cocaine self-administration by GBR 12909 has been reported, 118 and in baboons, the behaviorally effective doses of GBR 12909 produce high occupancies of DAT as measured by PET imaging. 131 Behavioral evaluation of selected GBR 12909 analogs have been reported wherein some but not all demonstrated behavioral profiles that were similar to the parent drug.…”

Section: Behavioral Evaluation Of Gbr 12909 and Its Analogues As Compmentioning

confidence: 99%

“…115 Additional modifications of the terminal phenyl ring of both GBR 12909 and 12935 by replacement with various heterocycles resulted in numerous novel and potent dopamine uptake inhibitors. 118,119 These heterocyclic analogues presumably possessed lower lipophilicities than the corresponding parent compounds, and thus may have more favorable bioavailability and pharmacokinetic profiles. On this line, a series of oxygenated analogues were prepared as well as their esterified pro-drugs for potential use as extended release agents.…”

Section: Gbr 12909 and Its Analoguesmentioning

confidence: 99%

“…131 Behavioral evaluation of selected GBR 12909 analogs have been reported wherein some but not all demonstrated behavioral profiles that were similar to the parent drug. 118 One study investigated a decanoate derivative of one of the oxygenated GBR 12909 analogs described above in sustaining decreases in cocaine-maintained responding in rhesus monkeys. 132 The results of this study showed that a single injection of this agent provided sustained and selective (over food) suppression of cocaine-maintained responding for nearly 30 days.…”

Section: Behavioral Evaluation Of Gbr 12909 and Its Analogues As Compmentioning

confidence: 99%

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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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Section: Behavioral Evaluation Of Gbr 12909 and Its Analogues As Compmentioning

confidence: 99%

Section: Gbr 12909 and Its Analoguesmentioning

confidence: 99%

Section: Behavioral Evaluation Of Gbr 12909 and Its Analogues As Compmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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“…Importantly, the concentration of GBR 12909 (1 μM) used to inhibit DAT in striatum in the current study was based on numerous competition assays in studies of [ 3 H]DA uptake into striatal synaptosomes (e.g., Rothman et al, 1994), and this concentration is 1000-fold higher than the reported K i value for inhibition of [ 3 H]DA uptake into striatal synaptosomes (e.g., Matecka et al, 1997). Current follow-up experiments determined a K i value of 0.21 ± 0.01 μM for GBR 12909 inhibition of [ 3 H]5-HT uptake into hippocampal synaptosomes (data not shown), suggesting that the concentration of GBR 12909 used to inhibit DAT in striatal synaptosomes may have also affected 5-HT uptake via SERT.…”

Section: Discussionmentioning

confidence: 98%

The promiscuity of the dopamine transporter: Implications for the kinetic analysis of [3H]serotonin uptake in rat hippocampal and striatal synaptosomes

2007

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SummaryEvidence indicates that monoaminergic neurotransmitter transporters are promiscuous, transporting substrates other than their cognate neurotransmitters. For example, serotonin is transported by the dopamine transporter (DAT) under conditions in which serotonin transporter (SERT) activity is eliminated (e.g., pharmacological inhibition). We performed a kinetic analysis of [ 3 H]serotonin uptake in rat striatal synaptosomes (expressing DAT and SERT) and hippocampal synaptosomes (expressing SERT, but not DAT). Nonspecific [ 3 H]serotonin uptake was defined as the amount of uptake remaining in the presence of fluoxetine (10 μM) or paroxetine (0.05 μM). In hippocampal synaptosomes, K m and V max values for [ 3 H]serotonin uptake did not differ whether fluoxetine or paroxetine was used to define nonspecific uptake. However, in striatal synaptosomes, both K m and V max values for [ 3 H]serotonin uptake were greater when fluoxetine, rather than paroxetine, was used to define nonspecific uptake. These data suggest that, at the concentrations employed, fluoxetine inhibits serotonin uptake at both DAT and SERT, whereas paroxetine only inhibits serotonin uptake at SERT. Thus, when DAT is inhibited by GBR 12909, kinetic parameters for serotonin uptake via SERT in striatum are not different from those obtained in hippocampus. These findings have important implications regarding the analysis of monoaminergic reuptake in brain regions exhibiting heterogeneous transporter expression.

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“…The complete list of analogs, their experimental DAT and SERT binding affinity, as K i , and pK i (DAT/SERT) are shown in Tables 1A and 1B. 15,17,[46][47][48][49] The experimental pK i (DAT/SERT) in the table was calculated from the following equation: (1) Binding experiments were performed in the Rothman laboratory using identical protocols for all the analogs. 15, 17, 46-49 The K i value is nearly identical to the IC 50 value under these experimental conditions.…”

Section: Selection Of Analogsmentioning

confidence: 99%

DAT/SERT selectivity of flexible GBR 12909 analogs modeled using 3D-QSAR methods

Gilbert¹,

Boos²,

Dersch³

et al. 2007

Bioorganic & Medicinal Chemistry

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The dopamine reuptake inhibitor GBR 12909 (1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine, 1) and its analogs have been developed as tools to test the hypothesis that selective dopamine transporter (DAT) inhibitors will be useful therapeutics for cocaine addiction. This 3D-QSAR study focuses on the effect of substitutions in the phenylpropyl region of 1. CoMFA and CoMSIA techniques were used to determine a predictive and stable model for the DAT/serotonin transporter (SERT) selectivity (represented by pK i (DAT/SERT)) of a set of flexible analogs of 1, most of which have eight rotatable bonds. In the absence of a rigid analog to use as a 3D-QSAR template, six conformational families of analogs were constructed from six pairs of piperazine and piperidine template conformers identified by hierarchical clustering as representative molecular conformations. Three models stable to y-value scrambling were identified after a comprehensive CoMFA and CoMSIA survey with Region Focusing. Test set correlation validation led to an acceptable model, with q 2 = 0.508, standard error of prediction = 0.601, two components, r 2 = 0.685, standard error of estimate = 0.481, F value = 39, percent steric contribution = 65, and percent electrostatic contribution = 35. A CoMFA contour map identified areas of the molecule that affect pK i (DAT/SERT). This work outlines a protocol for deriving a stable and predictive model of the biological activity of a set of very flexible molecules.

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Heteroaromatic Analogs of 1-[2-(Diphenylmethoxy)ethyl]- and 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as High-Affinity Dopamine Reuptake Inhibitors

Cited by 59 publications

References 35 publications

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

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

The promiscuity of the dopamine transporter: Implications for the kinetic analysis of [3H]serotonin uptake in rat hippocampal and striatal synaptosomes

DAT/SERT selectivity of flexible GBR 12909 analogs modeled using 3D-QSAR methods

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