Targeting voltage-gated calcium channels for the treatment of neuropathic pain: a review of drug development

Pexton, T; Moeller-Bertram, Tobias; Schilling, Jan M.; Wallace, Mark

doi:10.1517/13543784.2011.600686

Cited by 54 publications

(34 citation statements)

References 83 publications

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“…Both drugs, however, are encumbered with problematic side effects as well as difficult dosing regimens [53; 54; 57; 67]. The development of novel CaV2.2-targeted drugs with improved efficacy and therapeutic index is highly desirable [50]. …”

Section: Introductionmentioning

confidence: 99%

(S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology

Moutal

Chew

Yang

et al. 2016

Pain

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Chronic pain affects the life of millions of people. Current treatments have deleterious side effects. We have advanced a strategy for targeting protein interactions which regulate the N-type voltage-gated calcium (CaV2.2) channel as an alternative to direct channel block. Peptides uncoupling CaV2.2 interactions with the axonal collapsin response mediator protein 2 (CRMP2) were antinociceptive without effects on memory, depression, and reward/addiction. A search for small molecules that could recapitulate uncoupling of the CaV2.2–CRMP2 interaction identified (S)-lacosamide [(S)-LCM], the inactive enantiomer of the Food and Drug Administration–approved antiepileptic drug (R)-lacosamide [(R)-LCM, Vimpat]. We show that (S)-LCM, but not (R)-LCM, inhibits CRMP2 phosphorylation by cyclin dependent kinase 5, a step necessary for driving CaV2.2 activity, in sensory neurons. (S)-lacosamide inhibited depolarization-induced Ca2+ influx with a low micromolar IC50. Voltage-clamp electrophysiology experiments demonstrated a commensurate reduction in Ca2+ currents in sensory neurons after an acute application of (S)-LCM. Using constellation pharmacology, a recently described high content phenotypic screening platform for functional fingerprinting of neurons that uses subtype-selective pharmacological agents to elucidate cell-specific combinations (constellations) of key signaling proteins that define specific cell types, we investigated if (S)-LCM preferentially acts on certain types of neurons. (S)-lacosamide decreased the dorsal root ganglion neurons responding to mustard oil, and increased the number of cells responding to menthol. Finally, (S)-LCM reversed thermal hypersensitivity and mechanical allodynia in a model of postoperative pain, and 2 models of neuropathic pain. Thus, using (S)-LCM to inhibit CRMP2 phosphorylation is a novel and efficient strategy to treat pain, which works by targeting specific sensory neuron populations.

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Section: Introductionmentioning

confidence: 99%

(S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology

Moutal

Chew

Yang

et al. 2016

Pain

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“…Peptides from fish and worm-hunting marine cone snails (for example, ω-conotoxin) selectively target N-type calcium channels that are critical for nociceptive transmission. Ziconotide represents successful translation of one of these peptides to the clinic (16). Other peptides from marine species are also being assessed for their potential as pain therapeutics (17–19).…”

Section: Preclinical Challenges In Identification Of Pain Targetsmentioning

confidence: 99%

Lost but making progress—Where will new analgesic drugs come from?

et al. 2014

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There is a critical need for effective new pharmacotherapies for pain. The paucity of new drugs successfully reaching the clinic calls for a reassessment of current analgesic drug discovery approaches. Many points early in the discovery process present significant hurdles, making it critical to exploit advances in pain neurobiology to increase the probability of success. In this review, we highlight approaches that are being pursued vigorously by the pain community for drug discovery, including innovative preclinical pain models, insights from genetics, mechanistic phenotyping of pain patients, development of biomarkers, and emerging insights into chronic pain as a disorder of both the periphery and the brain. Collaborative efforts between pharmaceutical, academic, and public entities to advance research in these areas promise to de-risk potential targets, stimulate investment, and speed evaluation and development of better pain therapies.

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“…The synthesis and structure-activity relationships (SAR) of small molecule blockers of N-type calcium channels have been extensively reviewed elsewhere [88,108,109]. This section will focus on more recent advances (2009 to present) in the discovery and development of small molecule N-type calcium channel blockers.…”

Section: Small Molecule N-type Blockersmentioning

confidence: 99%

“…Early studies to evaluate Z160 [14] in humans have been hampered by the molecule's poor aqueous solubility and consequent limited bioavailability in initial formulations [108,109]. Early studies to evaluate Z160 [14] in humans have been hampered by the molecule's poor aqueous solubility and consequent limited bioavailability in initial formulations [108,109].…”

Section: Z160mentioning

confidence: 99%

Recent Progress in the Discovery and Development of N-Type Calcium Channel Modulators for the Treatment of Pain

Lee¹

2014

Progress in Medicinal Chemistry

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Targeting voltage-gated calcium channels for the treatment of neuropathic pain: a review of drug development

Cited by 54 publications

References 83 publications

(S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology

(S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology

Lost but making progress—Where will new analgesic drugs come from?

Recent Progress in the Discovery and Development of N-Type Calcium Channel Modulators for the Treatment of Pain

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