The Discovery of an Unusually Selective and Novel Cocaine Analog: Difluoropine. Synthesis and Inhibition of Binding at Cocaine Recognition Sites

Meltzer, Peter C.; Liang, Anna Y.; Madras, Bertha K.

doi:10.1021/jm00039a014

Cited by 88 publications

(125 citation statements)

References 17 publications

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“…It is noteworthy that previous studies have suggested the existence of different modes of binding for benztropine and cocaine. These compounds are likely to be positioned in a binding site in a different way, based on structure-activity studies showing that the difference between R-and S-enantiomers observed in analogs of cocaine was reversed in fluorinated analogs of 2-carbomethoxybenztropine (35). Vaughan et al (36) observed incorporation of a benztropine-based photoaffinity ligand into a DAT domain encompassing transmembrane regions 1 and 2, as opposed to incorporation of a cocaine-based ligand into a domain containing transmembrane helices 4 -7, again suggesting that the orientation of the compounds in the binding site may differ (35).…”

Section: Table III Potency Of Compounds In Reducing Mtset-induced Inhmentioning

confidence: 99%

“…These compounds are likely to be positioned in a binding site in a different way, based on structure-activity studies showing that the difference between R-and S-enantiomers observed in analogs of cocaine was reversed in fluorinated analogs of 2-carbomethoxybenztropine (35). Vaughan et al (36) observed incorporation of a benztropine-based photoaffinity ligand into a DAT domain encompassing transmembrane regions 1 and 2, as opposed to incorporation of a cocaine-based ligand into a domain containing transmembrane helices 4 -7, again suggesting that the orientation of the compounds in the binding site may differ (35). Moreover, there are differences in the psychomotor stimulant-like effects of cocaine and benztropine in rodents (37) and self-administration of these compounds in rhesus monkeys (38).…”

Section: Table III Potency Of Compounds In Reducing Mtset-induced Inhmentioning

confidence: 99%

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The Uptake Inhibitors Cocaine and Benztropine Differentially Alter the Conformation of the Human Dopamine Transporter

Reith¹,

Berfield²,

Wang³

et al. 2001

Journal of Biological Chemistry

110

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The inhibitor benztropine was unique in its inability to protect Cys-135. Moreover, whereas cocaine, WIN, mazindol, and dopamine enhanced the reaction of Cys-90 with MTSET, benztropine had no effect on this reaction. These two features combine to give benztropine its weak potency in protecting ligand binding to wild-type DAT from MTSET. These results indicate that different inhibitors of DAT, such as cocaine and benztropine, produce different conformational changes in the transporter. There are differences in the psychomotor stimulant-like effects of these compounds, and it is possible that the different behavioral effects of these DAT inhibitors stem from their different molecular actions on DAT.

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Section: Table III Potency Of Compounds In Reducing Mtset-induced Inhmentioning

confidence: 99%

Section: Table III Potency Of Compounds In Reducing Mtset-induced Inhmentioning

confidence: 99%

The Uptake Inhibitors Cocaine and Benztropine Differentially Alter the Conformation of the Human Dopamine Transporter

Reith¹,

Berfield²,

Wang³

et al. 2001

Journal of Biological Chemistry

110

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“…1; Table 2). Of eight possible isomers previously characterized, difluoropine emerged as the most potent within a series of benztropine analogs (Meltzer et al, 1994), and it was 15 times more potent than its progenitor benztropine (Table 2). In further distinction to benztropine, difluoropine displayed low affinity for the muscarinic cholinergic receptor (Tables 2 and 3).…”

Section: Resultsmentioning

confidence: 99%

“…We focused on eight novel, chemically diverse analogs of the phenyltropane CFT, or WIN 35,428, which exhibits high affinity for the DAT ( Table 3; Madras et al, 1989Madras et al, , 1996Madras et al, , 2003Kaufman and Madras, 1991;Meltzer et al, 1994Meltzer et al, , 2001. Selection criteria were initially restricted to high DAT affinity and DAT:SERT selectivity, because SERT inhibitors reportedly attenuate DAT inhibitor-mediated improvements in locomotor activity (Hansard et al, 2002a).…”

mentioning

confidence: 99%

Dopamine Transporter (DAT) Inhibitors Alleviate Specific Parkinsonian Deficits in Monkeys: Association with DAT Occupancy in Vivo

Fahey¹,

Goulet²,

Lin³

et al. 2006

J Pharmacol Exp Ther

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Viable dopamine neurons in Parkinson's disease express the dopamine transporter (DAT) and release dopamine (DA). We postulated that potent DAT inhibitors, with low affinity for the serotonin transporter (SERT), may elevate endogenously released extracellular dopamine levels to provide therapeutic benefit. The therapeutic potential of eight DAT inhibitors was investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated cynomolgus monkeys (Macaca fascicularis), with efficacy correlated with DAT occupancy as determined by positron emission tomography imaging in striatum. Four potent DAT inhibitors, with relatively high norepinephrine transporter, but low SERT affinities, that occupied the DAT improved activity in parkinsonian monkeys, whereas three high-affinity DAT inhibitors with low DAT occupancy did not. 2␤-Carbomethoxy-3␣-(3,4-dichlorophenyl)-7␤-hydroxy-8-methyl-8-azabicyclo[3.2.1.]octane (O-1163) occupied the DAT but had short-lived pharmacological effects. The benztropine analog difluoropine increased general activity, improved posture, reduced body freeze, and produced sleep disturbances at high doses. (1R)-2␤-(1-Propanoyl)-3␣-(4-fluorophenyl)tropane (O-1369) alleviated parkinsonian signs in advanced parkinsonian monkeys, by increasing general activity, improving posture, reducing body freeze, and sedation, but not significantly reducing bradykinesia or increasing locomotor activity. In comparison with the D 2 -D 3 DA receptor agonist quinelorane, O-1369 elicited oral/facial dyskinesias, whereas quinelorane did not improve posture or reduce balance and promoted stereotypy. In conclusion, DAT inhibitors with therapeutic potential combine high DAT affinity in vitro and high DAT occupancy of brain striatum in vivo with enduring daytime effects that do not extend into the nighttime. Advanced parkinsonian monkeys (80% DAT loss) respond more effectively to DAT inhibitors than mild parkinsonian monkeys (46% DAT loss). The therapeutic potential of dopamine transport inhibitors for Parkinson's disease warrants preclinical investigation.Parkinson's disease (PD) is the most common of the neurodegenerative movement disorders, with approximately 1% of the population older than 65 years presenting with this progressive disease. Disease symptoms are caused by degeneration of dopamine neurons in the substantia nigra, with significant losses of dopamine and the dopamine transporter (DAT) in the basal ganglia (e.g., Kish et al., 1988;Kaufman and Madras, 1991)

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“…Although studies of structure-activity relationships (SAR) did not provide a comprehensive picture of the binding interaction to DAT at molecular level yet, studies on cocaine and its tropane analogues (see Fig. 1) 8,[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] showed that two…”

Section: Introductionmentioning

confidence: 99%

3-Aza-6,8-dioxabicyclo[3.2.1]octanes as new enantiopure heteroatom-rich tropane-like ligands of human dopamine transporter

Cini

Danieli

Menchi

et al. 2006

Bioorganic & Medicinal Chemistry

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Abstract-CNS diseases such as Parkinson, schizophrenia, and attention deficit hyperactivity disorder (ADHD) are characterized by a significant alteration of dopamine transporter (DAT) density. Thus, the development of compounds that are able to selectively interact with DAT is of great interest. Herein we describe the design and synthesis of a new set of 3-aza-6,8-dioxabicyclo[3.2.1]octanes having a tropane-like structure with additional heteroatoms at positions 3 and 6. The compounds were evaluated for their in vitro receptor binding properties toward human dopamine (hDAT) and serotonin (hSERT) transporters using [

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The Discovery of an Unusually Selective and Novel Cocaine Analog: Difluoropine. Synthesis and Inhibition of Binding at Cocaine Recognition Sites

Cited by 88 publications

References 17 publications

The Uptake Inhibitors Cocaine and Benztropine Differentially Alter the Conformation of the Human Dopamine Transporter

The Uptake Inhibitors Cocaine and Benztropine Differentially Alter the Conformation of the Human Dopamine Transporter

Dopamine Transporter (DAT) Inhibitors Alleviate Specific Parkinsonian Deficits in Monkeys: Association with DAT Occupancy in Vivo

3-Aza-6,8-dioxabicyclo[3.2.1]octanes as new enantiopure heteroatom-rich tropane-like ligands of human dopamine transporter

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