2002 Medicinal Chemistry Division Award Address:  Monoamine Transporters and Opioid Receptors. Targets for Addiction Therapy

A BSTRACTThe discovery and preclinical development of selective dopamine reuptake inhibitors as potential pharmacotherapies for treating cocaine addiction are presented. The studies are based on the hypothesis that a dopamine reuptake inhibitor is expected to partially substitute for cocaine, thus decreasing cocaine self-administration and minimizing the craving for cocaine. This type of indirect agonist therapy has been highly effective for treating smoking addiction (nicotine replacement therapy) and heroin addiction (methadone). To be an effective pharmacotherapy for cocaine addiction, the potential drug must be safe, long-acting, and have minimal abuse potential. We have developed several 3-phenyltropane analogs that are potent dopamine uptake inhibitors, and some are selective for the dopamine transporter relative to the serotonin and norepinephrine transporters. In animal studies, these compounds substitute for cocaine, reduce the intake of cocaine in rats and rhesus monkeys trained to selfadminister cocaine, and have demonstrated a slow onset and long duration of action and lack of sensitization. The 3-phenyltropane analogs were also tested in a rhesus monkey selfadministration model to defi ne their abuse potential relative to cocaine. Based on these studies, 3 ␤ -(4-chlorophenyl)-2 ␤ -[3-(4 ' -methylphenyl)isoxazol-5-yl]tropane (RTI-336) has been selected for preclinical development.

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“…It is hoped that one of these compounds will be useful as a medication for treating cocaine addicts without deleterious side effects. 12 …”

Section: Introductionmentioning

confidence: 99%

Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse

Carroll

Howard²,

Howell

et al. 2006

AAPS J

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“…Reflecting the central role of monoamine transporters in cocaine abuse and addiction, the tropane class of competitive inhibitors, including cocaine, has been extensively studied as monoamine transporter inhibitors. Cocaine itself is a potent and nonselective inhibitor of SERT, NET, and DAT, but several closely related analogs have been developed with improved affinity and selectivity across the monoamine transporters (Carroll, 2003;Jin et al, 2008a). Important examples include 2␤-carbomethoxy-3␤-(4-fluorophenyl)tropane (WIN 35,428), which has selectivity for DAT over NET and SERT and (Ϫ)-2␤-carbomethoxy-3␤-(4-iodophenyl)tropane (RTI-55), which has selectivity for SERT and DAT over NET (Table 3).…”

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confidence: 99%

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

et al. 2011

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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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2002 Medicinal Chemistry Division Award Address: Monoamine Transporters and Opioid Receptors. Targets for Addiction Therapy

Cited by 82 publications

References 161 publications

Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse

Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

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

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