l-Cysteine based N-type calcium channel blockers: structure–activity relationships of the C-terminal lipophilic moiety, and oral analgesic efficacy in rat pain models

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

doi:10.1016/s0960-894x(02)00456-0

Cited by 21 publications

(4 citation statements)

References 14 publications

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“…The recent scientific and patent literature has reported a wide range of uncharged compounds effective as N-type calcium channel blockers (Abbadie et al, 2010; Pajouhesh et al, 2012; Patel et al, 2015; Seko et al, 2002; Seko et al, 2003; Shao et al, 2012; Yamamoto and Takahara, 2009; Zamponi et al, 2009), and many of these have structures that can be modified into cationic versions. Our results suggest that making cationic versions of such molecules that have external blocking activity on calcium and sodium channels may be an unexpected new route to identifying new powerful agents well-suited for both treating pain from injury and surgery and inflammatory conditions with a neurogenic component.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation

Lee

Talbot

et al. 2019

eLife

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“…1,3,19-21 A significant literature exists documenting efforts to define existing and new molecular entities active at non-L-type channels. [22][23][24][25][26][27] From such studies have appeared both nonselective and selective agents, the latter showing modest in vivo and in vitro potency, but apparently inadequate to enter clinical studies.…”

Section: Voltage-gated Calcium Channels As New Drug Targetsmentioning

confidence: 99%

Drug Targets in the Voltage-Gated Calcium Channel Family: Why Some Are and Some Are Not

Triggle

2003

ASSAY and Drug Development Technologies

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The L-type calcium channel antagonists have been, and continue to be, a very successful group of therapeutic agents targeted at cardiovascular disorders, notably angina and hypertension. The discovery that the voltage-gated calcium channels are a large and widely distributed family with important roles in both the peripheral and central nervous systems has initiated a major search for drugs active at other calcium channel types directed at disorders of the central nervous system, including pain, epilepsy, and stroke. These efforts have not been therapeutically successful thus far, and small molecule equivalents of the L-type blockers nifedipine, diltiazem, and verapamil directed at non-L-type channels have not been found. The underlying reasons for this are discussed together with suggestions for new directions, including fertility control, oxygen-sensitive channels, and calcium channel activators.

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“…In the dorsal horn of the spinal cord, these channels control the release of glutamate and neuropeptides such as substance P (Smith et al, 2002), thereby supporting pain transmission via afferent A␤, A␦, and C fibers to neurons projecting to the thalamus (Krarup, 2003). Consequently, inhibition of N-type channels via activation of opioid receptors or by N-type channel antagonists mediates analgesia in animals and humans (Hu et al, 1999;Scott et al, 2002;Seko et al, 2002;Staats et al, 2004). Moreover, Ca V 2.2 channel knock-out mice have decreased pain responses in models of neuropathic and inflammatory pain (Hatakeyama et al, 2001;Kim et al, 2001;Saegusa et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Differential Role of N-Type Calcium Channel Splice Isoforms in Pain

Altier¹,

Dale²,

Kisilevsky³

et al. 2007

Journal of Neuroscience

148

144

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N-type calcium channels are essential mediators of spinal nociceptive transmission. The core subunit of the N-type channel is encoded by a single gene, and multiple N-type channel isoforms can be generated by alternate splicing. In particular, cell-specific inclusion of an alternatively spliced exon 37a generates a novel form of the N-type channel that is highly enriched in nociceptive neurons and, as we show here, downregulated in a neuropathic pain model. Splice isoform-specific small interfering RNA silencing in vivo reveals that channels containing exon 37a are specifically required for mediating basal thermal nociception and for developing thermal and mechanical hyperalgesia during inflammatory and neuropathic pain. In contrast, both N-type channel isoforms (e37a-and e37b-containing) contribute to tactile neuropathic allodynia. Hence, exon 37a acts as a molecular switch that tailors the channels toward specific roles in pain.

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l-Cysteine based N-type calcium channel blockers: structure–activity relationships of the C-terminal lipophilic moiety, and oral analgesic efficacy in rat pain models

Cited by 21 publications

References 14 publications

Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation

Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation

Drug Targets in the Voltage-Gated Calcium Channel Family: Why Some Are and Some Are Not

Differential Role of N-Type Calcium Channel Splice Isoforms in Pain

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