Novel Conformationally Constrained Tropane Analogues by 6-<i>e</i><i>ndo-trig</i> Radical Cyclization and Stille Coupling − Switch of Activity toward the Serotonin and/or Norepinephrine Transporter

Hoepping, Alexander; Johnson, Kenneth M.; George, Clifford; Flippen‐Anderson, Judith L.; Kozikowski, Alan P.

doi:10.1021/jm0001121

Cited by 88 publications

(57 citation statements)

References 29 publications

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“…Cocaine analogs and chemical libraries of more than 300,000 compounds have been screened for differential activities in inhibiting cocaine analog binding and in blocking dopamine uptake (Chalon et al, 1999;Javanmard et al, 1999;Hoepping et al, 2000). Studies with these small molecules have identified the importance of many features of cocaine's structure for its ability to block dopamine uptake or to inhibit cocaine analog binding by DAT.…”

mentioning

confidence: 99%

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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confidence: 99%

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

Lin

Uhl

2002

Mol Pharmacol

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“…Two possible approaches for the conversion of 61 to 62 were the Heck cyclization 38–41 and a radical initiated cyclization. 42, 43 We found that intramolecular cyclization of 61 using reductive Heck conditions similar to that used for intermolecular coupling 20 (palladium diacetate, potassium formate, and tetrabutyl ammonium chloride in dimethylformamide at 90 °C) provided the hexahydro-7,10-methanopyrrolo-2-[1,2-b]-2,6-naphthyridine 62 in 45% yield. Hydrolysis of 62 using refluxing 3 N hydrochloric acid gave a 90% yield of the 3-amino analog 63 .…”

Section: Synthesis Of Bridged and Fused Ring Analogs Of Epibatidinementioning

confidence: 98%

Epibatidine Analogs Synthesized for Characterization of Nicotinic Pharmacophores—A Review

Carroll¹

2009

HETEROCYCLES

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In 1992 Daly and co-workers reported the isolation of a new natural product, epibatidine. Future studies showed that epibatidine was an nAChR ligand with analgesic potency 200–400 times greater than that of morphine. However, its potential as a new drug was limited by its toxic side effects, probably resulting from its activity at a number of nAChR subtypes. Epibatidine’s unique structure and potent activity made it an ideal lead structure for the development of nAChR ligands with reduced side effects and better nAChR subtype selectivity. This review presents the synthetic methods we have used to synthesize a number of epibatidine agonists, antagonists, and mixed agonists/antagonists to better characterize the α4β2 nAChR pharmacophore and hopefully provide compounds that have potential for treating nicotine addiction.

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“…The tricyclic antidepressants form a group that comprises several potent and selective NET inhibitors [46,47]. Other groups, in which potent NET inhibitors may be found are monocyclics [48][49][50][51], bicyclics [52] and tropane derivatives [53,54].…”

Section: Net Inhibitorsmentioning

confidence: 99%

Development of Radioligands for Imaging of Brain Norepinephrine Transporters In Vivo with Positron Emission Tomography

Schou¹,

Pike²,

Halldin³

2007

CTMC

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In the central nervous system (CNS) and in the periphery, specific proteins (transporters) are responsible for the regulation of the synaptic concentrations of the major monoamine neurotransmitters, noradrenaline (NE), serotonin (5-HT) and dopamine (DA). Several reports have shown that the expression of these transporters within the CNS may be altered in patients with certain neurodegenerative or neuropsychiatric disorders. Therefore, in the CNS the monoamine transporters are major targets for existing and developmental drugs. The best known drugs targeting these transporters are the selective 5-HT reuptake inhibitors (SSRIs) (e.g. citalopram, Celexa) that are most frequently used in the treatment of clinical depression. Selective NE reuptake inhibitors (NRIs) have also found use for the treatment of depression and other conditions such as attention deficit hyperactivity (ADHD) disorder. Given that the NE transporter (NET) is also a binding site for cocaine and drugs of abuse, there is a great need for a probe to assess the densities of NET in vivo by brain imaging with either positron emission tomography (PET) or single photon emission tomography (SPET). PET in particular has the potential to measure NET densities quantitatively and with high resolution in the human brain in vivo. The quality of a PET image depends crucially on the radioligand used in the emission measurement. Commonly used radionuclides in PET radioligands are carbon 11 (t(1/2) = 20.4 min) and fluorine-18 (t(1/2) = 109.8 min). This review specifically summarizes the present status of the development of (11)C- or (18)F-labeled ligands as tools for imaging NET in brain with PET in support of neuropsychiatric clinical research and drug development.

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Novel Conformationally Constrained Tropane Analogues by 6-endo-trig Radical Cyclization and Stille Coupling − Switch of Activity toward the Serotonin and/or Norepinephrine Transporter

Cited by 88 publications

References 29 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

Epibatidine Analogs Synthesized for Characterization of Nicotinic Pharmacophores—A Review

Development of Radioligands for Imaging of Brain Norepinephrine Transporters In Vivo with Positron Emission Tomography

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