Treating Pain with Calcium and Sodium Channel Blockers

Calcium Channel Blockers

The Zalicus Ion channel technology identifies state-dependent Ion channel modulators to achieve analgesic efficacy with superior selectivity and safety profiles
Increased (high-frequency) neuronal activity in neuropathic pain drives channels into an inactivated channel state that can be selectively antagonized by our compounds
Compounds designed to target the inactivated channel state will selectively modulate neurons undergoing high-frequency firing while sparing low-frequency firing neurons where channels may be predominantly in the closed state.
The Zalicus Ion channel targets are well-validated in the treatment of pain.
Zalicus has multiple Ion channel compounds undergoing preclinical efficacy evaluation.

Improved Calcium Channel Blockers
through Electrophysiological Screening

Zalicus has created a differentiated model for the discovery of new calcium channel blocking compounds that overcomes the serious issue of selectivity in calcium channel blocker drug discovery. Zalicus utilizes a proprietary electrophysiological screening process to generate drug candidates with much greater levels of specificity than other systems. This capability enables the discovery of targeted state and frequency dependant blockers and it is anticipated that by improving selectivity, compounds with greatly enhanced safety and tolerability profiles can be developed.

Zalicus (formerly Neuromed) was the first company to discover that the various calcium channels in the nervous system are encoded by a family of distinct genes, and, recognizing the potential pharmaceutical significance of the N-type and T-type calcium channels, Zalicus devised innovative screening platforms and discovered initial proprietary calcium channel blocker product candidates. Building on this work, Zalicus is currently pursuing calcium channel programs targeting the N-type and the T-type calcium channel gene subtypes and may potentially develop mixed N/T-type calcium channel product candidates.

Sodium Channel Blockers

In addition to the N-type and T-type calcium channels being targeted for pain, Zalicus has been actively pursuing another class of Ion channel for pain drug discovery and therapeutic intervention. Sodium channels (abbreviated Na_V) crucially regulate pain signaling by mediating sodium ion currents that contribute to the excitability of both peripheral pain-sensing neurons and also neurons within the spinal cord that relay pain signals to the brain. Several distinct types of sodium channels are important for setting the threshold and influencing the frequency, sustainability and intensity of pain signaling.

Of the ten sodium channel genes found in humans, the Nav1.7 and Nav1.8 types are of particular interest related to multiple chronic pain conditions as they are validated in both humans and commonly used preclinical models. For example, in humans naturally occurring loss-of-function genetic mutations in the Na_V1.7 channel lead to the complete abolition of pain sensation while other gain-of-function Na_V1.7 mutations cause severe chronic pain syndromes. Further, in animal models it has been shown that the suppression of either Na_V1.7 or Na_V1.8 channels reduces various kinds of acute and neuropathic pain.

Addressing these attractive targets for pain intervention, Zalicus has utilized its considerable expertise in Ion channels to develop an in-house R & D program to design, characterize and develop novel, orally available agents that modulate the physiological functioning of Na_V1.7 and Na_V1.8 channels. The goal is to specifically target the increased firing and hypersensitivity in peripheral and spinal cord neurons that express Na_V1.7 and Na_V1.8 and that are associated with chronic inflammatory and neuropathic pain.

Representing the considerable progress that Zalicus has made to date, a pipeline of preclinical agents shown to affect Na_V1.7 and Na_V1.8 channels has been generated. A number of these new compounds have been found to both reduce the excitability of neurons and to reverse pain hypersensitivity in animal models of acute and neuropathic pain. The Na_V1.7 and Na_V1.8 blocking compound Z212 uniquely acts by preferentially attenuating hyperexcitable neurons while largely sparing normally firing neurons. Zalicus hopes that targeting sodium channels in the peripheral and central nociceptive signaling pathways through a unique mechanism of action will lead to novel classes of safe and effective pain therapeutics.

Zalicus believes that the targeting of selective sodium channels both complements the existing N-type and T-type calcium channel pain programs and further by integrating many preclinical aspects of the programs, provides for cost-effective, value-added synergies to its drug discovery platform.

Calcium channels are involved in the control and regulation of many critical cell pathways and are attractive drug targets. In order to carry out the multiple physiological functions that calcium channels help regulate, the human genome encodes distinct types of calcium channels. Of particular relevance for pharmaceutical development, each of the different types of calcium channels is known to perform distinct physiological functions and offers the opportunity to target specific drugs to specific calcium channels and human disease indications. However, because of the ubiquity of the genetically related calcium channel family members, compounds with low specificity for their targets have the potential for cross-reactivity leading to potential side effects. As a result, compounds with high specificity for specific subtypes of calcium channels are very important in the development of product candidates that will be both safe and efficacious.

Terrance P. Snutch, PhD, FRSC, DSc (hon)

Dr. Snutch Dr. Snutch, a Senior Scientific Advisor to Zalicus and the founder of Neuromed, is a professor in the Michael Smith Laboratories at the University of British Columbia. He was the first scientist in the world to describe the molecular basis for clinically important calcium channels in the cardiovascular, endocrine and nervous systems.

Dr. Snutch's contributions have been recognized internationally with numerous awards, including the International Albrecht Fleckenstein Award, the Killam Research Prize, the Steacie Prize, and induction into the Royal Society of Canada. He was named 2004 Researcher of the Year by BC Biotech and has received the BC Innovation Council's New Frontiers in Research Award. Most recently, Dr. Snutch received an Honorary Doctorate of Science from Simon Fraser University.

See List of Selected Publications

T-Type Calcium Channel Blockers That Attenuate Thalamic Burst Firing and Suppress Absence Seizures. Science and Translational Medicine, 15 February 2012, Vol 4 Issue 121. (PDF)

Hildebrand et al. Identification of sodium channel isoforms that mediate action potential firing in lamina I/II spinal cord neurons. Journal of Molecular Pain 2011, 7:67. (PDF)

Newman et al. Auranofin Protects against Anthrax Lethal Toxin-Induced Activation of the Nlrp1b Inflammasome. American Society for Microbiology: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Mar. 2011, p. 1028–1035 Vol. 55, No. 3. (PDF)

Hildebrand ME et al. A novel slow-inactivation-specific ion channel modulator attenuates neuropathic pain. PAIN® (2011), doi:10.1016/j.pain.2010.12.035 (PDF)

Analgesic Effects of a Substituted N-Triazole Oxindole (TROX-1), a State-Dependant Cav2 Calcium Channel Blocker. Journal of Pharmacology Experimental Therapeutics 334:545-555. (PDF)

Treatments for Neuropathic Pain Differentially Affect Delayed Matching Accuracy by Macaques: Effects of Amitriptyline and Gabapentin. Pain 148:446-453. Epub 2010 Jan 25 (PDF)

Functional Coupling Between mGluR1 and Cav3.1 T-type Calcium Channels Enhances Cerebellar Purkinje Cell Excitability and Local Signaling. Journal of Neuroscience 29:9668-9682. (Abstract)

A Fluorescence-based High Throughput Screening Assay for the Identification of T-type Calcium Channel Blockers. Assay and Drug Development Technologies 7:266-280. (PDF)

Block of voltage-gated calcium channels stimulates dopamine release in rat mesocorticolimbic system. Neuropharmacology 56: 984-993. (PDF)

Cav2.1 P/Q-type Calcium Channel Alternative Splicing Affects the Functional Impact of Familial Hemiplegic Migraine Mutations: Implications for Calcium Channelopathies. Channels 3(2): 110-121. (PDF)

Role of voltage calcium channels in ascending pain pathway. Brain Research Reviews 60(1):84-9 (PDF)

Block of Voltage-Gated Calcium Channels Attenuates Ethanol-Induced Intoxication, Place Preference, Self-Administration and Relapse. Journal of Neuroscience 28(45): 11712-11719. (PDF)

Selective Inhibition of Cav3.3 T-type Ca Channels by Gαq/11-Coupled Muscarinic Acetylcholine Receptors. Journal of Biological Chemistry, 282:21043-21055. (PDF)

CaV3 T-type calcium channel isoforms differentially distribute to somatic and dendritic compartments in rat central neurons. Eur J Neurosci. 24: 2581-2594. (PDF)

Temperature dependence of T-type calcium channel gating. Neuroscience, 142:1031-1042. (PDF)

Genetic heterogeneity in paroxysmal nonkinesigenic dyskinesia. Neurology, 66: 1588-1590 (PDF)

Specific T-type calcium channel isoforms are associated with distinct burst phenotypes in deep cerebellar nuclear neurons. Proc. Natl. Acad Sci. (USA), 103(14): 5555-5560. (PDF)

Functional Analysis of Cav3.2 T-type calcium channel mutations linked to childhood absence epilepsy. Epilepsia, 47(3): 655-658. (PDF)

Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates a major role in nociception. EMBO Journal, 24:315-324. (PDF)

Malaysian Siblings with Friedreich Ataxia and Chorea: A Novel Deletion in Frataxin Gene. Canadian Journal of Neurological Sciences, 31: 383-386. (PDF)

The IUPHAR Compendium of Voltage-Gated Ion Channels. Edited by WA Catterall, KG Chandy, GA Gutman. P. 44-50. (PDF)

Residue G1326 of the N-type calcium channel α1B subunit controls reversibility of ϖ-conotoxin GVIA and MVIIA block. Journal of Biological Chemistry 276: 15728-15735. (PDF)