Inhibition and inactivation of presynaptic cholinergic markers using redox-reactive choline analogs

Patel, Phenil J.; Messer, William S.; Hudson, Richard

doi:10.1021/jm00065a012

Cited by 14 publications

(13 citation statements)

References 19 publications

(34 reference statements)

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“…Concentration-dependent inhibition of Ch transport by 6 and 7 was established from their dose-response curves. Plots of the initial rate of Ch uptake versus log [6] and log [7] are shown in Figure 2. Table 1 IC 50 values for 6 and 7 were determined to be 76 and 21 μM, respectively.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of choline transport by redox-active cholinomimetic bis-catechol reagents

Cai¹,

Mukherjee²,

Tillekeratne³

et al. 2007

Bioorganic & Medicinal Chemistry

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Both N,N′-(2,3-dihydroxybenzyl)-N,N,N′,N′-tetramethyl-1,6-hexanediamine dibromide (DTH,6) and N,N′-(2,3-dihydroxybenzyl)-N,N,N′,N′-tetramethyl-1,10-decanediamine dibromide (DTD, 7), which are symmetrical bis-catechol substituted hexamethonium and decamethonium analogues, respectively, were found to inhibit high affinity choline transport in mouse brain synaptosomes. Inhibitory properties were evaluated using an extraordinarily sensitive capillary electrophoresis method employing electrochemical detection at an enzyme-modified microelectrode. Dose-response curves were generated for each inhibitor and IC 50 values were determined to be 76 μM for 6 and 21 μM for 7. Lineweaver-Burk analysis revealed that both molecules inhibit high affinity choline uptake by a mixed inhibition mechanism. The K I values for 6 and 7 were determined to be 73 ± 1 and 31 ± 2 μM, respectively. The inhibition properties were further compared to a series of mono-catechol analogues, 3-[(trimethylammonio)methyl]catechol (1), N,N-dimethylepinephrine (4) and 6-hydroxy-N,N-dimethylepinephrine (5), as well as the well-characterized hemicholinium inhibitors, hemicholinium-15 (HC-15, 8) and hemicholinum-3 (HC-3, 9).

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Section: Resultsmentioning

confidence: 99%

Inhibition of choline transport by redox-active cholinomimetic bis-catechol reagents

Cai¹,

Mukherjee²,

Tillekeratne³

et al. 2007

Bioorganic & Medicinal Chemistry

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“…These molecules are choline homologs, which have an affinity for cholinergic sites and a redox-active catechol portion that may inactivate the cholinergic binding sites. This view is also supported by animal behavioral studies that indicate neurotoxic effects occur with these reagents [24]. Measurement of the specific concentration ranges of the chemical agents that induce neuronal degradation and analysis of the site-specific chemical events that are triggered will define the potency and selectivity of the chemical agents toward the cholinergic pathway.…”

Section: Introductionmentioning

confidence: 91%

“…A suspension of synaptosomes was prepared following the general procedure of Gray and Whittaker [32] as modified by Patel et al [24]. The detailed procedure has been described elsewhere [11].…”

Section: Measurement Of Choline Uptake In Synaptosomesmentioning

confidence: 99%

“…We are specifically interested in understanding the changes in concentration of ACh and Ch in presynaptic sites under conditions of selective inhibition of the high-affinity choline uptake channel by a new class of quaternary ammonium catechol-based chemical agents [22][23][24][25][26][27] that exhibit neurotoxic effects at presynaptic cholinergic sites. One such agent is 3-[(trimethylammonio)methyl]catechol (TMC, Fig.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of the inhibition of choline uptake in synaptosomes by capillary electrophoresis with electrochemical detection

Barkhimer¹,

Kirchhoff²,

Hudson

et al. 2002

Electrophoresis

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A direct method for evaluating choline uptake by the high-affinity choline transport system in synaptosomes was developed using capillary electrophoresis (CE) with electrochemical (EC) detection. On-column EC detection of choline and the internal standard, butyrylcholine, was accomplished with a 25 microm platinum electrode modified with the enzymes, choline oxidase and acetylcholinesterase. Choline uptake was evaluated as a function of choline concentration and a KM value of 1.7 microM was determined. The method was also used to evaluate a new class of redox affinity inhibitors of choline transport. In particular, the effectiveness of 3-[(trimethylammonio)methyl]catechol (TMC) as an inhibitor of choline uptake was examined independently and relative to the inhibition of the well-known inhibitor of choline transport, hemicholinium-3. The IC50 and KI for TMC were determined to be 30 microM and 14 microM, respectively. The combination of the selectivity and sensitivity afforded by CEEC provides a relatively straightforward approach for monitoring choline transport in synaptosomes.

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“…Previous research in the catechols analogues reported that the diphenol such as compound 2 with a 3,4-dihydroxy substitution in the benzene ring is more sensitive to the oxidation than a 2,3-dihydroxy substitution such as in compound 3. [13] The unstable property of compound 2 might induces more side reactions and decreases its cross-linking capacity.…”

mentioning

confidence: 99%

Synthesis and Oxidation‐Induced DNA Cross‐Linking Capabilities of Bis(catechol) Quaternary Ammonium Derivatives

Song¹,

Weng²,

Weng³

et al. 2008

Chemistry A European J

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Many antitumor agents such as cisplatin and nitrogen mustard work through a DNA cross-linking mechanism, in which interstrand cross-linking is especially important. [1] These agents covalently bind to the DNA duplex and inhibit both replication and transcription in tumor cells eventually killing them.[2] However, the application of these drugs has been limited by their toxic side effects in normal cells. The possibility of selectively destroying the DNA of tumor cells by induction has been given much attention in medicinal research. Inducible DNA cross-linking agents have provided a promising method for specifically damaging tumor cells. [3] The inducible formation of o-quinone methide (o-QM) as a precursor of antitumor agents has been reported by many groups because o-QM is highly reactive with DNA.[4] Our group has reported several efficient DNA cross-linking agents derived from an o-QM intermediate induced by a biphenol quaternary ammonium structure [5] and a biphenol selenide structure.[6] Recently, Kodadeks group reported that biotinylated catechol derivatives could cross-link proteins via an o-quinone intermediate induced by NaIO 4 . [7] The quinone intermediate induced by the oxidation of a catechol appears to be a promising agent for studying the properties of complicated biological complexes, [8] and moreover, this oxidative activity can be carried out by a ubiquitous enzyme, that is, tyrosinase.[9] Encouraged by their reports, we designed and synthesized a new family of DNA crosslinking agents: bisA C H T U N G T R E N N U N G (catechol) quaternary ammonium derivatives (Figure 1). We found that they could cross-link DNA potently via an o-quinone intermediate induced by oxidation.Compounds 1-3 are composed of two catechol monomers acting as DNA cross-linking units, and are joined by different linkers that act as DNA binding units. In order to achieve high affinity to DNA, positive charged linkers and quaternary ammonium were considered for use. Furthermore, aliphatic and aromatic chains were investigated to determine which of them resulted in favorable cross-linking reactions, and to determine the relationship between agent flexibility and DNA cross-linking abilities. These compounds were prepared as shown in the supporting information. All new compounds were fully characterized by NMR spectroscopy and HRMS analysis.The DNA-DNA cross-linking abilities of compounds 1-3 were firstly studied using tyrosinase as oxidative agent. Tyrosinase is a binuclear copper enzyme occurs in all organisms, which can catalyze the oxidation of catechols to qui- [a]

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Inhibition and inactivation of presynaptic cholinergic markers using redox-reactive choline analogs

Cited by 14 publications

References 19 publications

Inhibition of choline transport by redox-active cholinomimetic bis-catechol reagents

Inhibition of choline transport by redox-active cholinomimetic bis-catechol reagents

Evaluation of the inhibition of choline uptake in synaptosomes by capillary electrophoresis with electrochemical detection

Synthesis and Oxidation‐Induced DNA Cross‐Linking Capabilities of Bis(catechol) Quaternary Ammonium Derivatives

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