Structure–Activity Study and Analgesic Efficacy of Amino Acid Derivatives as N-Type Calcium Channel Blockers

Seko, Takuya; Kato, Masashi; Kohno, Hiroshi; Ono, Shota; Hashimura, Kazuya; Takimizu, Hideyuki; Nakai, Katsuhiko; Maegawa, Hitoshi; Katsube, Nobuo; Toda, Masaaki

doi:10.1016/s0960-894x(01)00414-0

Cited by 18 publications

(7 citation statements)

References 12 publications

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“…Figure 1 (inset) shows the neutral molecule that we designed for this purpose. Its structure is based on a scaffold of a family of molecules with blocking activity against N-type calcium channels described by Seko et al (2001), although it is not identical to any of the compounds they described. This molecule, which we call NNCB-2 (‘NNCB’ for ‘neutral N-type calcium channel blocker’) has a secondary amine group that can be readily converted to a quaternary form to form a cationic molecule, which we call CNCB-2 (‘CNCB’ for ‘cationic N-type calcium channel blocker’).…”

Section: Resultsmentioning

confidence: 99%

“…We expected that CNCB-2 would have selectivity for N-type calcium channels, because the parent compound was based on a family described as being selective N-type calcium channel inhibitors (Seko et al, 2001). Surprisingly, however, we found that CNCB-2 also inhibits sodium channels with external application, acting even more potently on sodium channels than on N-type calcium channels.…”

Section: Resultsmentioning

confidence: 99%

“…NNCB-2 (3-Cyclopentylmethylsulfanyl-2-(3,3-dimethyl-butylamino)- N -(4-methoxy-benzyl)-propionamide) and CNCB-2 ([2-Cyclopentylmethylsulfanyl-1-(4-methoxy-benzylcarbamoyl)-ethyl]−(3,3-dimethyl-butyl)-dimethyl-ammonium; chloride salt) were designed based on the scaffold described by Seko et al (2001) and custom synthesized (Sundia MediTech Co, Ltd.). Structures were verified by NMR and liquid chromatography mass spectrometry.…”

Section: Methodsmentioning

confidence: 99%

“…Spurred by the relative lack of knowledge about the pharmacology of N-type channel blockers and by the possibility of pursuing a strategy of large-pore channel-mediated drug entry to selectively block transmitter release from nociceptors, we explored the channel blocking properties of a cationic N-type channel inhibitor based on a scaffold described for a group of neutral N-type channel blockers (Seko et al, 2001). Surprisingly, we found that the cationic molecule effectively inhibits Cav2.2 channels when administered externally, as well as internally, and actually acts more rapidly with external application.…”

Section: Introductionmentioning

confidence: 99%

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Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation

Lee

Talbot

et al. 2019

eLife

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Voltage-dependent sodium and calcium channels in pain-initiating nociceptor neurons are attractive targets for new analgesics. We made a permanently charged cationic derivative of an N-type calcium channel-inhibitor. Unlike cationic derivatives of local anesthetic sodium channel blockers like QX-314, this cationic compound inhibited N-type calcium channels more effectively with extracellular than intracellular application. Surprisingly, the compound is also a highly effective sodium channel inhibitor when applied extracellularly, producing more potent inhibition than lidocaine or bupivacaine. The charged inhibitor produced potent and long-lasting analgesia in mouse models of incisional wound and inflammatory pain, inhibited release of the neuropeptide calcitonin gene-related peptide (CGRP) from dorsal root ganglion neurons, and reduced inflammation in a mouse model of allergic asthma, which has a strong neurogenic component. The results show that some cationic molecules applied extracellularly can powerfully inhibit both sodium channels and calcium channels, thereby blocking both nociceptor excitability and pro-inflammatory peptide release.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation

Lee

Talbot

et al. 2019

eLife

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“…The pyrene modified HA (PyrHA) is further synthesized by esterification of DEHA with 1-pyrenebutyric acid by using EDC as the coupling reagent. 32 In ethanol solution, PyrHA exhibits four absorption peaks at 312, 326, 342 and 514 nm, respectively. The absorption peaks at 312, 326 and 342 nm can be assigned to the π-π* transitions located on the pyrene subunits, and the absorption peak at 514 nm is attributed to π-π* transition located on the HA subunit.…”

Section: Synthesis Of the Y 3+ Coordination Polymer Of Pyrhamentioning

confidence: 99%

The effect of amphiphilic polymers on the association, morphology and photophysical properties of hypocrellin coordination polymer/fullerene assemblies

Liu

Gao

et al. 2014

Photochem Photobiol Sci

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The yttrium coordination polymer of pyrene modified hypocrellin A (Y(3+)-PyrHA) is synthesized and characterized. The methoxydiglycol malonate modified fullerene can be included in the cavity of Y(3+)-PyrHA in organic solution and buffer solution containing amphiphilic polymers, such as polyvinyl pyrrolidone (PVP), pluronic F127 and P123. The interaction between an amphiphilic polymer and Y(3+)-PyrHA plays an important role in controlling the size and morphology of Y(3+)-PyrHA/fullerene. TEM images of Y(3+)-PyrHA/fullerene in 1% F127 and P123 show nanoparticles in the size range 10-60 nm, while TEM images of Y(3+)-PyrHA/fullerene in 1% PVP display large-scale aggregation. Singlet oxygen is generated by irradiation of the polymer solution of Y(3+)-PyrHA/fullerene in the presence of oxygen. The electron paramagnetic resonance (EPR) spin trapping and 9,10-dimethoxyanthracene-2-sulfonic acid sodium salt (MAS) photooxidation results suggest that in 1% P123 solution Y(3+)-PyrHA/fullerene exhibits a higher singlet oxygen quantum yield than Y(3+)-PyrHA and the corresponding fullerene.

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Stroke Therapy

Nantermet

Shalen

Shankar

et al. 2010

Burger's Medicinal Chemistry and Drug Discovery

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Structure–Activity Study and Analgesic Efficacy of Amino Acid Derivatives as N-Type Calcium Channel Blockers

Cited by 18 publications

References 12 publications

Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation

Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation

The effect of amphiphilic polymers on the association, morphology and photophysical properties of hypocrellin coordination polymer/fullerene assemblies

Stroke Therapy

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