STRATEGY OF N-TYPE CALCIUM CHANNEL BLOCKERS AS NOVEL THERAPEUTIC TARGET FOR THE TREATMENT OF CHRONIC AND NEUROPATHIC PAIN

1. STRATEGY OF N-TYPE CALCIUM CHANNEL BLOCKERS AS NOVEL THERAPEUTIC
TARGET FOR THE TREATMENT OF CHRONIC AND NEUROPATHIC PAIN
MR. ANKUSH BISWAS*, MR. ROHAN PALB AND DR. CHOWDHURY MOBASWAR HOSSAINC
*BENGAL SCHOOL OF TECHNOLOGY, SUGANDHA, HOOGHLY
[B = ASSISTANT PROFESSOR (PHARMACOLOGY & TOXICOLOGY), GLOBAL COLLEGE OF PHARMACEUTICAL TECHNOLOGY,
KRISHNANAGAR, NADIA]
[C = PROFESSOR AND PRINCIPAL (PHARMACOLOGY & TOXICOLOGY), BENGAL SCHOOL OF TECHNOLOGY, SUGANDHA, HOOGHLY]
INTRODUCTION
• A calcium channel is an ion channel which shows selective permeability
to calcium ions. It is sometimes synonymous as voltage-gated calcium channel,
although there are also ligand-gated calcium channels.
• Calcium channel α1, β, and α2δ subunits, and their topology.
N-TYPE CALCIUM CHANNEL
• Biochemical purification of native N-type channels using cone snail peptide toxins as
affinity ligands show the channel is a hetero-oligomeric complex consisting of α1B-
(Cav2.2), β-, and α2δ-subunits.
• N-type calcium channels are localized to synaptic nerve terminals in laminae 1 and
2 of the dorsal horn where their opening results in the release of neurotransmitters
such as glutamate and substance P.
• Domain structure of the 1B subunit of the N-type (Cav2.2) Ca2+ channel.
N-TYPE CALCIUM CHANNEL BLOCKERSPATHOPHYSIOLOGY OF NEUROPATHIC AND
CHRONIC PAIN
ROLE OF N-TYPE CALCIUM CHANNEL BLOCKER IN
NEUROPATHIC AND CHRONIC PAIN
• N-type calcium channel blockers play a large role in pain regulation. To block
a voltage-gated channel, the voltage current that activates the channels need
to be stopped. These toxins and blockers generally function by modulating G-
Protein Couple receptors (GPCR) that mediate the N-type Calcium channels.
FUTURE DIRECTIONS
 A major source of this molecular diversity arises from alternatively spliced N-
VSCC mRNAs, which yield NVSCCs with distinct neuronal localizations and,
perhaps, functional properties.
 The functional properties of N-VSCCs can also be differentially affected by
selective association with auxiliary subunits for which there are multiple
genes and multiple splice variants, as well All these structurally variant
multimolecular N-VSCC complexes have the potential for possessing
differential pharmacologies, including differential sensitivities to the numerous
N-VSCC-blocking omega-conopeptides that exist and/or those yet to be
discovered or engineered, as well.
 One ω-conopeptide, CVID or AM-336, which is very similar in amino acid
sequence to ziconotide, is antinociceptive in rats but is reported to have a
smaller effect on blood pressure and produce less shaking activity than
ziconotide at anti-nociceptive doses. AM-336 is currently in phase 2 clinical
trials in Australia for chronic pain.
 As the physiological roles of the various N-VSCC splice variants become
better understood, the possibility of rational design of safer, more effective
splice variant-selective conopeptide based NCCBs becomes more likely.
ACKNOWLEDGEMENT
I would like to express my special thanks of gratitude to Principal sir “Dr.
Chowdhury Mobaswar Hossain” and “Mr. Rohan Pal” for their able guidance
and support in completing my presentation.
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